THETWO TORTOITUUS MAKULTUURIMINE20180264122A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0264122 A1 Zipp et al. (43 ) Pub . Date : Sep . 20 , 2018 (54 ) CANNABINOID GLYCOSIDE PRODRUGS Related U . S . Application Data AND METHODS OF SYNTHESIS (60 ) Provisional application No . 62/ 363, 808, filed on Jul. 18 , 2016 , provisional application No. 62 / 245 , 928 , (71 ) Applicant: Vitality Biopharma, Inc, Los Angeles , filed on Oct. 23 , 2015 , provisional application No. CA (US ) 62 / 222 , 144 , filed on Sep . 22 , 2015 . ( 72 ) Inventors : Brandon J . Zipp , Roseville , CA (US ) ; Publication Classification Janee M . Hardman , Fair Oaks , CA (51 ) Int. CI. (US ) ; Robert T . Brooke , El Segundo , A61K 47/ 54 (2006 . 01) CA (US ) A61K 31/ 352 (2006 .01 ) ( 52 ) U .S . CI. CPC ...... A61K 47/ 549 (2017 . 08 ); A61K 9 /0019 (73 ) Assignee : Vitality Biopharma, Inc. , Los Angeles, ( 2013. 01 ); A61K 31/ 352 (2013 . 01 ) CA (US ) (57 ) ABSTRACT ( 21) Appl. No. : 15 / 762, 180 The present invention relates to cannabinoid glycoside pro drugs suitable for site - and tissue - specific delivery of can ( 22 ) PCT Filed : Sep . 22, 2016 nabinoid molecules . The present invention also relates to methods of forming the cannabinoid glycoside prodrugs ( 86 ) PCT No. : PCT/ US2016 /053122 through glycosyltransferase mediated glycosylation of can $ 371 (c )( 1 ), nabinoid molecules . (2 ) Date : Mar. 22 , 2018 Specification includes a Sequence Listing .

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CANNABINOID GLYCOSIDE PRODRUGS and other tissues , and different forms of glycosides may AND METHODS OF SYNTHESIS therefore provide unique pharmacokinetic profiles, includ ing formulations that target delivery of specific diseased FIELD OF THE INVENTION areas, or targeted release at locations that can promote or [0001 ] The present invention pertains to the field of drug restrict systemic absorption of the cannabinoids and other development and in particular to novel cannabinoid glyco compounds described herein .Many biologically active com side prodrugs and methods for their production by enzyme pounds are glycosides, including members of classes of compounds such as hormones , antibiotics , sweeteners , alka mediated carbohydrate transfer . loids , and flavonoids. While it is generally accepted that BACKGROUND glycosides will be more water- soluble than the aglycones , literature reviews have analyzed structure -activity relation [ 0002 ] Phytocannabinoids from Cannabis sativa have ships and determined that it is nearly impossible to define a long been used for altering mental states , but recent findings general pattern for the biological activities of glycosides have illuminated the potential of specific cannabinoid com pounds for treatment and maintenance of various diseases across different classes of compounds (Kren 2008 ) . and conditions . Of particular importance is the non -psycho [ 0005 ] As with synthetic chemistry , in vivo detoxification tropic molecule cannabidiol (CBD ) which has potential strategies serve as another model for improving the solubil therapeutic application as an anti - psychotic , a neuropro ity of cannabinoids . CBD is glucuronidated in humans by tectant , and has potential for treatment of numerous other the liver glucosyltransferases, but to date only minor activity maladies ( Zuardi 2012 , luvone 2009 , for review Mechoulam has been demonstrated with UGT1A9 and UGT2B7 in in 2002 , respectively ) . One shortcoming of CBD is that it is vitro assays ( U . S . Pat. No . 8 ,410 ,064 ) . In vitro assays easily oxidized to THC and CBN derivatives by light, heat, showed that cannabinol (CBN ) is efficiently glucuronidated and acidic or basic conditions, and another detrimental by the Human UGT1A10 ( U . S . Pat . No . 8 ,410 ,064 ) . The attribute to CBD is that its extremely hydrophobic nature glucuronidation of CBD is one mechanism to increase CBD makes it difficult for formulation and delivery . Additionally, solubility and facilitate removal and excretion through the current pharmaceutical compositions of CBD and THC have kidneys . Searching for glucosyltransferase activity towards unpleasant organoleptic properties, and their hydrophobic cannabinoids , cannabinol was found to be glycosylated nature results in a lingering on the palate . when incubated with in vitro cell culture of Pinellia ternata [0003 ] Cannabinoids are extremely hydrophobic in nature , ( Tanaka 1993 ) . Similarly , cannabidiol was shown to be complicating their use in drug formulations . Non - covalent glycosylated when incubated with tissue cultures from methods have been found to improve the solubility of Pinellia ternata and Datura inoxia , yielding CBD - 6 - O - B cannabinoids by utilizing carrier carbohydrates such as D - glucopyranoside and CBD - ( 2 ', 6 ' ) - O - B - D - diglucopyrano cyclized maltodextrins ( Jarho 1998 ) . Covalent chemical side ( Tanaka 1996 ) . These biotransformation studies dem manipulations have produced novel CBD prodrugs with onstrate the potential for limited glycosylation of these two improved solubility (WO2009018389 , WO 2012011112 ) . compounds to occur by unknown plant glucosyltransferases , Even fluorine substituted CBD compounds have been cre and for them to be produced in minute quantities , but to date , ated through synthetic chemical manipulations in an effort to no specific plant glucosyltransferase proteins capable of functionalize CBD (WO2014108899 ) . The aforementioned glycosylation of cannabinoids have been identified , no can strategies were somewhat successful in improving the solu nabinoid glycosides been produced in large , purified quan bility of CBD , but they create unnatural compositions which tities, and the biological activity or pharmaceutical proper alter the composition and will release the unnatural prodrug ties of cannabinoid glycosides have never been moieties upon hydrolysis . characterized . [0004 ] A growing body of evidence shows that glycosides [0006 ] Cannabinoids contain a hydroxylated hydrophobic are capable of acting as prodrugs and also to have direct backbone , similar to the steviol backbone of steviol glyco therapeutic effects . Glycoside prodrugs may enable sides found in the Stevia rebaudiana plant. UGT76G1 is a improved drug bioavailability or improved drug pharma glucosyltransferase from Stevia that is capable of transfer cokinetics including more site - specific or tissue - specific ring a secondary glucose to the 3C -hydroxyl of the primary drug delivery , more consistent levels of drug in the plasma, glycosylation on both 013 -OH and C19 -COOH position of and sustained or delayed release of the drug . Site - specific the steviol glycoside , and thus its substrates include stevio delivery of steroid glycosides to the colon has previously Imonoside , stevioside, rubusoside, RebA , RebD , RebG , been demonstrated ( Friend 1985 , Friend 1984 ) , and could RebE , etc . (Richman et al. 2005 , Stevia First Corp unpub enable treatment of local disorders such as inflammatory lished work ). The substrate recognition site of UGT76G1 is bowel disease . Glycosylation of steroids enabled survival of capable of binding and glycosylating multiple steviol gly stable bioactive molecules in the acidic stomach environ cosides, but it was previously not known to have glycosy ment and delivery into the large intestine , where the agly lation activity towards any other glycosides , and there cones were liberated by glycosidases produced by colonic previously was no established activity of UGT76G1 towards bacteria , and then absorbed into the systemic circulation . any aglycone compounds at all. As UGT76G1 is capable of Glycosidases are also present universally in different tissues glycosylating steviol glycosides on the primary sugar ( Conchie 1959 ), so delivery of glycosides by methods that located on both C13 hydroxyl group and the C19 carboxyl bypass the digestive tract and colon , such as intravenous group it demonstrates bi- functional glycosylation . Cyclo delivery, will enable targeted delivery to other cells and dextrin glucanotransferase (CGTase , Toruzyme 3 .0L , tissues that have increased expression of glycosidases. In Novozymes Inc . ) is a member of the amylase family of addition , the distribution of alpha - glycosidase and beta enzymes and is best known for its ability to cyclize malto glycosidase enzymes differ throughout the intestinal tract dextrin chains. A lesser known activity of CGTase is dis US 2018 /0264122 A1 Sep . 20 , 2018 proportionation of linear maltodextrin chains and transfer to of fully disclosing preferred embodiments of the technology an acceptor sugar molecule (Li 2012 ). without placing limitations thereon . [ 0007 ] There are no known cannabinoid glycosides avail able as cannabinoid prodrugs . Nor is there a known method BRIEF DESCRIPTION OF THE FIGURES for the efficient regioselective production of cannabinoid 0014 ] FIG . 1A illustrates aglycones employed in the glycosides, which is necessary in order to produce large , glycosylation methods of the present invention . FIG . 1B purified quantities of individual glycosides and to assess illustrates the possible points of glycosylation on the agly their pharmaceutical properties , including evaluation of in cones. vivo drug pharmacokinetics and pharmacodynamics . To [0015 ] FIG . 2 illustrates possible products of the glyco solve the aforementioned problem , screening of glucosyl sylation of cannabidiol (CBD ). transferase enzymes from various organisms has been con [0016 ]. FIG . 3 illustrates possible products of the glyco ducted to identify candidates for the glycosylation of can sylation of cannabidivarin (CBDV ) . nabinoids, and to identify cannabinoid glycosides as [0017 ]. FIG . 4 illustrates possible rotational products of the potential prodrugs of cannabinoids, and as novel cannabi glycosylation of cannabidiol (CBD ) . noid compositions with novel properties and functions. [0018 ] FIG . 5 illustrates possible rotational products of the [0008 ] This background information is provided to reveal glycosylation of cannabidivarin (CBDV ) . information believed by the applicant to be of possible 10019 . FIG . 6 illustrates the proposed superpositioning of relevance to the present invention . No admission is neces the substrate cannabidiol (CBD ) in the catalytic site of sarily intended , nor should be construed , that any of the UGT76G1. preceding information constitutes prior art against the pres [0020 ] FIG . 7 illustrates possible products of the glyco ent invention . sylation of tetrahydrocannabinol (49 - THC ) . [0021 ] FIG . 8 illustrates possible products of the glyco SUMMARY OF THE INVENTION sylation of cannabinol (CBN ) . [0009 ] The present invention relates to novel cannabinoid [0022 ]. FIG . 9 illustrates possible products of the glyco glycoside prodrugs and methods for their production by sylation of arachidonoyl ethanolamide ( AEA ). enzyme- mediated carbohydrate transfer. [ 0023 ] FIG . 10 illustrates possible products of the glyco [0010 ] An object of the present invention is to provide a sylation of 2 - arachidonoyl ethanolamide ( 2 - AG ) . cannabinoid glycoside prodrug . In accordance with an 10024 ] FIG . 11 illustrates possible products of the glyco aspect of the present invention , there is provided a cannabi sylation of 1- arachidonoyl ethanolamide (1 - AG ). noid glycoside prodrug compound having formula ( I) : [0025 ] FIG . 12 illustrates possible products of the glyco sylation of N - docosahexaenoylethanolamine (DHEA ) . [0026 ] FIG . 13 illustrates possible products of the glyco (1 ) sylation of capsaicin . HO [0027 ] FIG . 14 illustrates possible products of the glyco sylation of vanillin . [ 0028 ] FIGS. 15A and 15B illustrate possible products of the glycosylation of curcumin . [0029 ] FIG . 16 is an HPLC linetrace of the reaction RO Y products of the glycosylation of CBD . [0030 ] FIG . 17 is an HPLC linetrace of the reaction OR products of the glycosylation of CBDV. 10031 ] FIG . 18 is an HPLC linetrace of the reaction wherein R is H , B - D - glucopyranosyl, or 3 - 0 - B - D - glucopy products of the glycosylation of A9 - THC . ranosyl- ß - D -glucopyranosyl ; R ' is H or B -D - glucopyrano [0032 ] FIG . 19 is an HPLC linetrace of the reaction syl, or 3 - 0 - B - D - glucopyranosyl- ß - D - glucopyranosyl; and A products of the glycosylation of CBN . is an aglycone moiety formed through reaction of a hydroxyl [0033 ] FIG . 20 is an HPLC linetrace of the reaction group on a cannabinoid compound , an endocannabinoid products of the glycosylation of 1 - AG and 2 - AG . compound , or a vanilloid compound , or a pharmaceutically [0034 FIG . 21 is an HPLC linetrace of the reaction compatible salt thereof. products of the glycosylation of synaptamide (DHEA ) . [0011 ] In accordance with another aspect of the present [0035 ] FIG . 22 is an HPLC linetrace of the reaction invention , there is provided a method for the site- specific products of the glycosylation of AEA . delivery of a cannabinoid drug to a subject, comprising the [0036 ] FIG . 23 is an HPLC linetrace of the reaction step of administering a cannabinoid glycoside prodrug in products of the glycosylation of vanillin . accordance with the present invention to a subject in need [0037 ] FIG . 24 is an HPLC linetrace of the reaction thereof. products of the glycosylation of capsaicin . [ 0012 ] In accordance with another aspect of the present [0038 ] FIG . 25 is an HPLC linetrace of the reaction invention , there is provided a method of producing a can products of the glycosylation of CBDgl (VB104 ) with the nabinoid glycoside, comprising incubating a cannabinoid glycosyltransferase UGT76G1. aglycone with one or more sugar donors in the presence of [0039 ] FIG . 26 is an HPLC linetrace of the reaction one or more glycosyltransferases . products of the glycosylation of CBDgl (VB104 ) with the [0013 ] Further aspects of the technology described herein glycosyltransferase Os03g0702000 will be brought out in the following portions of the speci [0040 ] FIG . 27 is a ' NMR spectrum of an isolated product , fication , wherein the detailed description is for the purpose VB104 , of the glycosylation of CBD . US 2018 /0264122 A1 Sep . 20 , 2018

[0041 ] FIG . 28 is a 'NMR spectrum of an isolated product, [0068 ] The term “ endocannabinoid ” is used in the present VB110 of the glycosylation of CBD . application to refer to compounds including arachidonoyl 0042 ] FIG . 29 is a plot of C18 retention times vs cLogP ethanolamide ( anandamide , AEA ) , 2 - arachidonoyl ethanol values for selected cannabinoids and cannabinoid glyco amide ( 2 - AG ) , 1 - arachidonoyl ethanolamide ( 1 - AG ) , and sides . docosahexaenoyl ethanolamide ( DHEA , synaptamide ), [0043 ] FIG . 30A is a graphical presentation of the results oleoyl ethanolamide (OEA ), eicsapentaenoyl ethanolamide , of the analysis of the small intestine extracts of a bioavail prostaglandin ethanolamide , docosahexaenoyl ethanol ability assay . amide, linolenoyl ethanolamide, 5 (2 ), 8 ( Z ), 11 ( Z ) - ei [0044 ] FIG . 30B is a graphical presentation of the results cosatrienoic acid ethanolamide (mead acid ethanolamide ) , of the analysis of the large intestine extracts of a bioavail heptadecanoul ethanolamide , stearoyl ethanolamide, doco ability assay saenoyl ethanolamide, nervonoyl ethanolamide , tricosanoyl ethanolamide , lignoceroyl ethanolamide, myristoyl ethano DETAILED DESCRIPTION OF THE lamide, pentadecanoyl ethanolamide, palmitoleoyl ethanol INVENTION amide, docosahexaenoic acid (DHA ) . Particularly preferred [0045 ] The following abbreviations are used throughout: endocannabinoids are AEA , 2 - AG , 1 - AG , and DHEA . [0046 ] CB Cannabinoid [0069 ] The term “ vanilloid ” is used in the present appli 10047 ] CBD Cannabidiol. cation to refer to compounds comprising a vanillyl group [0048 ] CBDV Cannabidivarin and which act on vanilloid receptors like TRPV1. “ Vanil 10049 ) CBG Cannabigerol loid ” compounds include , but are not limited to , vanillin , [0050 ) A9 - THC or THC Tetrahydrocannabinol capsaicin and curcumin . [0051 ] CBN Cannabinol [ 0070 ] As used herein , the term “ about ” refers to a [0052 ] CBNV Cannabinavarin + / - 10 % variation from the nominal value . It is to be [0053 ] CBDA Cannabidiolic acid understood that such a variation is always included in a [0054 ] THCV Tetrahydrocannabivarin given value provided herein , whether or not it is specifically [ 0055 ] UGT UDPG -dependent glucosyltransferase referred to . [ 0056 ] UDPG Uridine diphosphoglucose [0071 ] The term “ subject" or " patient” as used herein [0057 ] UDP Uridine diphosphate refers to an animal in need of treatment. In one embodiment , [0058 ) AEA Arachidonoyl ethanolamide ( aka , anand the animal is a human . amide) [0072 ] Unless defined otherwise , all technical and scien [0059 ] 2 - AG 2 - Arachidonoyl ethanolamide . tific terms used herein have the samemeaning as commonly [0060 ] 1 - AG 1 - Arachidonoyl ethanolamide . understood by one of ordinary skill in the art to which this [ 0061] DHEA N -Docosahexaenoylethanolamine (aka , invention belongs . synaptamide ) 10073 ]. In accordance with the present invention , cannabi [ 0062 ] SUS Sucrose synthase . noids , endocannabinoids and vanilloids are employed as [ 0063] The term " glucopyranoside ” is used for naming substrates for glucosyltransferases to which one or more molecules and is shorthand for a B - D - glucose attached sugar molecules are attached to create novel cannabinoid through the hydroxyl at the 1 - position ( the anomeric carbon ) glycoside prodrugs . The resulting cannabinoid glycoside of the glucose to the aglycone. prodrugs demonstrate site - specific or tissue - specific deliv [0064 ] The term “ aglycone” is used in the present appli ery, improved aqueous solubility for improved pharmaco cation to refer to the non -glycosidic portion of a glycoside logical delivery , and / or sustained or delayed release of the compound . cannabinoid , endocannabinoid and vanilloid drug mol [0065 ] The term “ prodrug” refers to a compound that , ecules. upon administration , must undergo a chemical conversion 100741. Also in accordance with the present invention , the by metabolic processes before becoming an active pharma cannabinoid glycoside prodrugs are converted upon hydro cological agent. lysis of the glycosidic bond to provide the active cannabi [0066 ] The term “ cannabinoid glycoside prodrug ” refers noid , endocannabinoid and vanilloid drug. Accordingly , the generally to the glycosides of cannabinoid compounds , present invention has demonstrated that glycosides with a endocannabinoid compounds and vanilloid compounds. The hydrophobic aglycone moiety undergo glucose hydrolysis in cannabinoid glycoside prodrug undergoes hydrolysis of the the gastrointestinal tract or in tissues having increased glycosidic bond , typically by action of a glycosidase, to expression of glycosidases, yielding the hydrophobic can release the active cannabinoid , endocannabinoid or vanilloid nabinoid compound in the targeted tissue or organ . compounds to a desired site in the body of the subject. The [0075 ] The glucose residues of glycosides are commonly cannabinoid glycoside prodrug of the present invention may acid -hydrolyzed in the stomach or cleaved by glycosidase also be referred to using the term “ cannaboside ” . enzymes in the intestinal tract , including by alpha - glycosi [ 0067 ] The term “ cannabinoid ” is used in the present dases and beta - glycosidases, which are expressed by intes application to refer generally to compounds found in can tinal microflora across different regions of the intestine . nabis and which act on cannabinoid receptors . “ Cannabi Accordingly , glycosides are hydrolyzed upon ingestion to noid ” compounds include , but are not limited to , cannabidiol release the desired compound into the intestines or target ( CBD ) , cannabidivarin (CBDV ) , cannabigerol (CBG ) , tet tissues . rahydrocannabinol ( A9 - THC or THC ) , cannabinol (CBN ) , [0076 ] In one embodiment, glycosylation of cannabinoid cannabidiolic acid (CBDA ) , and tetrahydrocannabivarin drugs provides cannabinoid glycoside prodrugs capable of ( THCV ) . Particularly preferred cannabinoids compounds persisting in the acidic stomach environment upon oral are CBD , CBDV , THC and CBN . administration , thereby allowing delivery of the prodrug into US 2018 /0264122 A1 Sep . 20 , 2018

the large intestine , where the cannabinoid aglycones can be -continued liberated by glycosidases produced by colonic bacteria . 10077 ] In one embodiment, glycosylation of cannabinoid drugs provides cannabinoid glycoside prodrugs suitable for targeted delivery to tissues having increased expression of wine glycosidases. Upon parenteral administration of the cannabi *1111 noid glycoside prodrug formulation to the subject , the can , or nabinoid aglycones are liberated by the glycosidases in the target tissues. [ 0078 ] It is also within the scope of the present invention that the cannabinoid glycoside prodrug are also useful as pharmaceutical agents without glucose cleavage, where they exhibit novel pharmacodynamic properties compared to the im parent compound alone . The increased aqueous solubility of the cannabinoid glycoside prodrugs of the present invention also enables new formulations for delivery in transdermal or aqueous formulations that would not have been achievable if formulating hydrophobic cannabinoid , endocannabinoid and vanilloid molecules . [0079 ] In one embodiment of the present invention , there are provided cannabinoid glycoside prodrug compounds having formula ( I) : [0082 ] wherein A " is :

HO .

HOM N

4 RO 0 - NG Opi or a pharmaceutically compatible salt thereof, wherein R is H , B - D - glucopyranosyl, or 3 - 0 -B - D -glucopyranosyl - ß - D glucopyranosyl; R ' is H or B - D -glucopyranosyl , or 3 - 0 - B m D - glucopyranosyl- B - D - glucopyranosyl; and A is an agly cone moiety formed through reaction of a hydroxyl group on in a cannabinoid compound , an endocannabinoid compound , OG or a vanilloid compound . [ 0080 ] In accordance with one embodiment of the present invention , A is A ', A " or A "" ; [0081 ] wherein A ' is : OG , or im

OG 1111 mi mm [0083 ] and wherein A '" is :

OG H3CO . 11111 mi 888888mi US 2018 /0264122 A1 Sep . 20 , 2018

- continued -continued

H3CO . H , or wine *1111 , or

H3CO LOCH3;

im mmpontba OG át wherein G is H , B - D -glucopyranosyl , 3 -O -B -D - glucopyra nosyl- B - D - glucopyranosyl , or B - D - glucopyranosyl- (1 - 3 ) B - D -glucopyranosyl - ( 1 - 3 )- D - glucopyranosyl ; or a phar maceutically compatible salt thereof. wherein G is B - D - glucopyranosyl, 3 - 0 - B - D - glucopyrano [ 0084 ] In accordance with one embodiment of the present syl- B - D - glucopyranosyl, or B - D - glucopyranosyl - ( 1 - 3 ) - B - D invention , the cannabinoid glycoside prodrug is a glycoside glucopyranosyl- ( 1 - 3 ) -D - glucopyranosyl. of a cannabinoid , wherein the prodrug has the formula (I ') : [ 0085 ] Compounds of Formula ( I' ) include the compounds listed in Tables 1 to 4 . [0086 ] Exemplary cannabidiol (CBD ) -glycosides falling (I ' ) within the scope of Formula ( I' ) , produced by the glycosy HO lation of CBD ( VB101) in accordance with the present invention , include : HO

VB102 RO OLA HO will wherein R is H , B - D - glucopyranosyl, or 3 - 0 - B - D - glucopy OH ranosyl- ß - D -glucopyranosyl ; R ' is H , B - D -glucopyranosyl , or 3 - O - B - D - glucopyranosyl - B - D - glucopyranosyl ; and will wherein A ' is : \ HO VB104 OH OH

1111

min Holiu . 111l0N

OHDH OG 11111 11

mi HO US 2018 /0264122 A1 Sep . 20 , 2018 9

- continued - continued VB106 H? H? VB112 OH

) 111

HOL HON "TO1111

HO Mno OH OH

HOM VB110 OH OH HO "VO1111 OH OH ??

-

HO11111

VB118 OH OH OH HO **

HO

VB108 till HOFF " HON" HO ???? 1111# OH TOH OH OH ?? .. HUN HO 111110L , and OH OH . HO .HOlte, HOI

CHO. HO US 2018 /0264122 A1 Sep . 20 , 2018 7

-continued -continued VB119 ?? ?? VB206 HO OH 111 HO11111

ON 1111l0

HO utON

61111 HO ??OH OH

HO11111" ! HO HO VB210 10111 HO HO HOH? H?HO 1111ON .Olitas HOI OH ,

. HO 1111 [ 0087] Exemplary cannabidivarin (CBDV ) -glycosides falling within the scope of Formula ( I' ) , produced by the glycosylation of CBDV (VB201 ) in accordance with the present invention , include : "HO1111 VB202 HO HO , 1 HO *VO111 OH OH

till

VB208 HO VB204 OH OH OH HO till

HON HOW .* 11110 ??OH OH , OH 11111 HOH? HOH? | | •111111

?? . HO US 2018 /0264122 A1 Sep . 20 , 2018 8 -continued -continued VB219 ?? ?? VB212 ?? ?? ? HO

-

? 100 '01111 ** 11llo

HO' til

HOW ON HO

HO ?? OH OH ?? ?? HUI

HO [0088 ] Exemplary tetrahydrocannabinol (A9 - THC ) - glyco sides falling within the scope of Formula (I ' ) , produced by the glycosylation of A9 - THC (VB301 ) in accordance with the present invention , include : VB218 HO VB302 OH VO " HOMHO. . HO HO‘ and V11 O tull1116

LUOHulo VB303 HO HO ?? JI IM ??OH OH HO HUI H OH 1111 HÕ . HO OH

*1111OH ° US 2018 /0264122 A1 Sep . 20 , 2018

-continued [0089 ] Exemplary cannabinol (CBN ) - glycosides falling VB304 OH OH within the scope of Formula ( I' ) , produced by the glycosy ] lation of CBN (VB401 ) in accordance with the present HO invention , include :

VB402 ?? HUN *HO1111 !! HOM OH HO

**1111

VB305 OH HO HO HO VB403 HO . HOW HUN ?? HOY"! HOT PUEand HO ?? ON1 11111 O HO 111 ??

VB308 HO

VB404 OH OH OH OH HO HO 11.

OIU .nntil HUN !! !HOT HO HO

**1111 US 2018 /0264122 A1 Sep . 20 , 2018

- continued wherein VB405 OH ?? R is H , B -D - glucopyranosyl, or II HOHON 3 -O - B - D - glucopyranosyl- B- D - glucopyranosyl; is H , B - D - glucopyranosyl , or 3 -0 - B - D -glucopyranosyl - B - D - glucopyranosyl; and [0091 ] wherein A " is : HO . 11ON OH mi and om

VB408 HO .

JUlitats OG mm ?? ?? HO OMe 11. E..

OG , or mi HOW .. TON content mm [0092 ] Compounds of Formula (I " ) include the com pounds listed in Tables 5 to 8 . [0093 ] Exemplary arachidonoyl ethanolamide (AEA ) - gly [0090 ] In accordance with one embodiment of the present cosides falling within the scope of Formula ( I " ) , produced by invention , the cannabinoid glycoside prodrug is a glycoside the glycosylation of AEA (VB501 ) in accordance with the of an endocannabinoid , the prodrug having the formula (I " ): present invention , include :

HO VB502 OH

1 HOm ON .

RO OMAT US 2018 /0264122 A1 Sep . 20 , 2018

- continued - continued VB503 VB505 OH OH HO HO OH OH HOLIS HOY ÕH I HOW YOb HOLOH111ON Y HO' OH " Y "HOM HO o 1 . and

VB506 HO HO VB504 HO HO . HOM

OH HOY?? 11ON H 111 OH OH . HO‘

[ 0094 ] Exemplary 2 - arachidonoyl ethanolamide ( 2 - AG ) glycosides falling within the scope of Formula ( I " ) , pro duced by the glycosylation of 2 - AG ( VB601) in accordance with the present invention , include :

VB602 VB603 HO HO , HOW ?? HO'

?? ??

OH VB605 VB608 ?? ?? HO HO HON HOW COOH

HO , JOHLOH OH LOH ?? POH HO OH US 2018 /0264122 A1 Sep . 20 , 2018 12

- continued VB607

OH HO HOSH > .. . HOHO‘'

OH HO

VB610 HO HO 111 HO

"HO

OH .

HOC

??

VB609 HO HUnita HOM

OH

OH HOOH

.. MUOH , and

HO - OH ?? US 2018 /0264122 A1 Sep . 20 , 2018

- continued VB615 OH OH III HO

IOH

OH

OH H CH

????? .

LOHOH

[ 0095 ] Exemplary 1 - arachidonoyl ethanolamide ( 1 - AG ) duced by the glycosylation of 1 - AG ( VB701) in accordance glycosides falling within the scope of Formula ( I" ) , pro with the present invention , include :

VB702 VB703 OH HOM . JOH OH OH , ?? **1111 OH

??

VB705 ?? HOM 1101

OH

TOH

?? US 2018 /0264122 A1 Sep . 20 , 2018 14

-continued VB708 VB707 OH

HOITOH OH OH , • OHHU HO OH JOH HOL HO OH ,HO HO HO

VB710 OH

HUN . #tillo

HO 01 HUllit , HOIH

HO

.8

HOS

NO HO

VB709 OH HUlitHOME . ONOH

OV HO siili

OH

OH , and OH

HO US 2018 /0264122 A1 Sep . 20 , 2018 15

- continued VB715 OH

PUN . .. tilo

OH

HOnlinHO ! . JOHON

OH OH

OH

?? 10 OH

[0096 ] Exemplary N - docosahexaenoylethanolamine (DHEA ) - glycosides falling within the scope of Formula ( I " ) , produced by the glycosylation of DHEA (VB801 ) in accor dance with the present invention , include :

VB802 OH Homme J1111OH OH ,

VB803 OH OH III HO

HOW sitt ON US 2018 /0264122 A1 Sep . 20 , 2018 16

-continued VB804 HO

HIOH O" OH ,

VB805 HO .

OH HO OH

tillo

OH , and

OH OH VB806 HO HO .

HUN

1 11111 ON

[0097 ] In accordance with one embodiment of the present wherein invention , the cannabinoid glycoside prodrug is a glycoside of a vanilloid , the prodrug having the formula ( I" ) : R is H , B -D - glucopyranosyl, or 3 - O - B - D - glucopyranosyl - B - D - glucopyranosyl; (I " ') [0098 ] R ' is H or B - D - glucopyranosyl, or 3 - 0 - B - D -glu HO . copyranosyl- B -D - glucopyranosyl; and , wherein A '" is : HO H3CO . min US 2018 /0264122 A1 Sep . 20 , 2018

- continued -continued

H3CO . OCH3.

H3CO H , or mmportta [0099 ] Compounds of Formula ( I '" ) include the com pounds listed in Tables 9 to 11 . [0100 ] Exemplary capsaicin - glycosides falling within the Hoe scope of Formula (I " ) , produced by the glycosylation of capsaicin (VB901 ) in accordance with the present invention , include:

VB902

HO boyling - ** HOW " OH

VB903

and IZ

HO

**! ! !

HO

HON * HO VB904

HO toring -

HO! Y *1111

OH HO OH US 2018 /0264122 A1 Sep . 20 , 2018 18

[0101 ] Exemplary vanillin - glycosides falling within the -continued scope of Formula (I ' " ), produced by the glycosylation of VB1005 vanillin (VB1001 ) in accordance with the present invention , include: VB1002 H , and

HO ?? HO: Y HORY in" HO OH OH VB1003 ** HO Y " #1110 ?? OH

HO?? VB1006 IH* H . HO

HO* ** Y * OHOH HO COM ** VB1004 HOY CH

HO

?? " HO * 11110 " OH OH HO OH [0102 ] Exemplary curcumin - glycosides falling within the Ols. scope of Formula ( I' ') , produced by the glycosylation of OH curcumin (VB1101 ) in accordance with the present inven tion , include :

VB1102 VB1103

OH , HO HO HO OH : ???? OCH3 OCH3 ???? HOY OH OH OHde prima POH OH US 2018 / 0264122A1 Sep . 20 , 2018

-continued VB1104

( H . HO 0CH3 OCH3 HOW .. ?? III F

IIIII

H0 VB1106

HO 0CH3 0CH3 - ?? 10H , OH

HO VB1108

H0 OH 0CH3 OCH3 Ho Y 11III10oH 10H , HO H0 H0 VB1109

? HO ??? 0CH3 ( CH3 : IIII??

HO 0H , ( H HO HO US 2018 /0264122 A1 Sep . 20 , 2018

-continued VB1110

HO OH OCH3 ???? , Holm LOH .

HO "INIO OH HONY POL*NOH HO VB1115

HO tilloOH OCH3 OCH3 - 0 OH

HO +11111 ( SH OH , OH

HO

VB1116

OH . HO OCH3 ???3 HO " Y " OH

HO

HON

HO HOHN HO US 2018 /0264122 A1 Sep . 20 , 2018 21

-continued VB1117

HO O HOS OCH3 ???3 - HON .. HOlim HO ( OH 0 — OH, OH HO111111 . HON IOS HO LosHO VB1121

0 0 HO 0 ???? OCH3 HOMILA 50Lt HO‘ HO ?? HO Y " OH

?? YOH OH

VB1123

HO ???? ???? HOI HO HO HO HO

OH , HO 11110 ?? US 2018 /0264122 A1 Sep . 20 , 2018 22

- continued VB1126

0 O HO HOS OCH3 ???3 . HOH HOW HO OH HO ..1111 HOLI . HUin LOH , HO OH SH OH VB1127

HO OCH3 OCH3

HOME Y POH ***111

?? OH , and OH . HUN

OH HO

,HOW HO

VB1129 O

o OH HO HOY Y ???? OCH3 HO " Y " OH HO HO HOWHOME Y HOIT 11110 ?? " 110 HO ! " Y " OH HO HO US 2018 /0264122 A1 Sep . 20 , 2018 23

[0103 ] In one embodiment, there is provided a method for variety of routes including but not limited to oral , topical, the site -specific delivery of a cannabinoid drug to a subject, rectal , parenteral, and intranasal administration . comprising the step of administering to a subject in need [0107 ] The pharmaceutical compositions may comprise thereof one or more cannabinoid glycoside prodrugs in from about 1 % to about 95 % of a cannabinoid glycoside accordance with the present invention . In one embodiment, prodrug of the invention . Compositions formulated for the site of delivery is the large intestine . In one embodiment, administration in a single dose form may comprise , for the site of delivery is the rectum . In one embodiment, the site example, about 20 % to about 90 % of the cannabinoid of delivery is the liver. In one embodiment, the site of glycoside prodrug of the invention , whereas compositions delivery is the skin . that are not in a single dose form may comprise , for [0104 ] In one embodiment, there is provided a method for example , from about 5 % to about 20 % of the cannabinoid facilitating the transport of a cannabinoid drug to the brain glycoside prodrug of the invention . Non - limiting examples through intranasal, stereotactic , or intrathecal delivery , or of unit dose forms include tablets , ampoules , dragees, sup delivery across the blood brain barrier of a subject compris positories, and capsules. ing administering a cannabinoid glycoside prodrug in accor 0108 ] In a preferred embodiment, the pharmaceutical compositions are formulated for oral administration . Phar dance with the present invention to a subject in need thereof. maceutical compositions for oral administration can be [ 0105 ] In accordance with the present invention , the can formulated , for example , as tablets , troches, lozenges , aque nabinoid glycoside prodrugs are useful in the treatment of ous or oily suspensions , dispersible powders or granules , conditions that benefit from or can be ameliorated with the emulsion hard or soft capsules, or syrups or elixirs . Such administration of a cannabinoid drug. Conditions that can be compositions can be prepared according to standard meth treated or ameliorated through the administration of can ods known in the art for the manufacture of pharmaceutical nabinoid glycoside prodrugs of the present invention , compositions and may contain one or more agents selected include but are not limited to , inflammatory bowel disease from the group of sweetening agents , flavouring agents , including induction of remission from Crohn ' s disease , and colouring agents and preserving agents in order to provide colitis and induction of remission from ulcerative colitis . pharmaceutically elegant and palatable preparations. Tablets Among the benefits that can be achieved through the admin contain the active ingredient in admixture with suitable istration of cannabinoid glycoside prodrugs of the present non - toxic pharmaceutically acceptable excipients including , invention are decreased inflammation of the intestines and for example , inert diluents , such as calcium carbonate , rectum , decreased pain in the intestines, rectum , as well as sodium carbonate , lactose , calcium phosphate or sodium decrease in neuropathic pain and abdominal pain , and inhi phosphate ; granulating and disintegrating agents , such as bition of proliferation or cytotoxicity against colorectal corn starch , or alginic acid ; binding agents , such as starch , cancer. Additional treatment indications, effects , or applica gelatine or acacia , and lubricating agents , such as magne tions for cannabinoids or cannabinoid glycosides may sium stearate , stearic acid or talc . The tablets can be include but are not limited to anorexia , nausea , emesis , pain , uncoated , or they may be coated by known techniques in wasting syndrome, HIV -wasting , chemotherapy induced order to delay disintegration and absorption in the gastro nausea and vomiting, epilepsy, schizophrenia , irritable intestinal tract and thereby provide a sustained action over a bowel syndrome , cramping , spasticity , seizure disorders , longer period . For example , a time delay material such as alcohol use disorders, substance abuse disorders, addiction , glyceryl monosterate or glyceryl distearate may be cancer, amyotrophic lateral sclerosis , glioblastoma multi employed to further facilitate delivery of the drug compound forme , glioma, increased intraocular pressure , glaucoma , to the desired location in the digestive tract. cannabis use disorders , Tourette 's syndrome, dystonia , mul [0109 ] Pharmaceutical compositions for oral use can also tiple sclerosis , white matter disorders, demyelinating disor be presented as hard gelatine capsules wherein the active ders , chronic traumatic encephalopathy , leukoencephalopa ingredient is mixed with an inert solid diluent , for example , thies , Guillain -Barre syndrome, inflammatory bowel calcium carbonate , calcium phosphate or kaolin , or as soft disorders , gastrointestinal disorders, bacterial infections , gelatine capsules wherein the active ingredient is mixed with MRSA , sepsis , septic shock , viral infections , arthritis , der water or an oil medium such as peanut oil , liquid paraffin or matitis , Rheumatoid arthritis , systemic lupus erythematosus , olive oil. anti - inflammatory , anti - convulsant, anti -psychotic , anti - oxi [0110 ] Pharmaceutical compositions formulated as aque dant , neuroprotective , anti - cancer , immunomodulatory ous suspensions contain the active compound ( s ) in admix effects, neuropathic pain , neuropathic pain associated with ture with one or more suitable excipients, for example, with post - herpetic neuralgia , diabetic neuropathy, shingles , suspending agents , such as sodium carboxymethylcellulose , burns, actinic keratosis, oral cavity sores and ulcers , post methyl cellulose , hydropropylmethylcellulose, sodium alg episiotomy pain , psoriasis , pruritis , gout, chondrocalcinosis , inate , polyvinylpyrrolidone, hydroxypropyl- ß - cyclodextrin , joint pain , fibromyalgia , musculoskeletal pain , neuropathic gum tragacanth and gum acacia ; dispersing or wetting postoperative complications. agents such as a naturally occurring phosphatide , for [0106 ] In one embodiment, the cannabinoid glycoside example, lecithin , or condensation products of an alkylene prodrug is administered in a pharmaceutical composition oxide with fatty acids , for example , polyoxyethyene stear further comprising a pharmaceutically acceptable carrier, ate , or condensation products of ethylene oxide with long diluent, excipient, or adjuvant. In one embodiment, the chain aliphatic alcohols , for example, hepta -decaethylene pharmaceutical compositions comprise one or more can oxycetanol, or condensation products of ethylene oxide with nabinoid glycoside prodrugs and one or more pharmaceuti partial esters derived from fatty acids and a hexitol for cally acceptable carriers, diluents , excipients and/ or adju example , polyoxyethylene sorbitol monooleate , or conden vants. For administration to a subject , the pharmaceutical sation products of ethylene oxide with partial esters derived compositions can be formulated for administration by a from fatty acids and hexitol anhydrides, for example , poly US 2018 /0264122 A1 Sep . 20 , 2018 24

ethylene sorbitan monooleate . The aqueous suspensions taneous injections , intravenous, intramuscular , intrathecal, may also contain one or more preservatives, for example intrasternal injection or infusion techniques . ethyl, or n -propyl p -hydroxy -benzoate , one or more colour [0117 ] Parenteral pharmaceutical compositions can be for ing agents , one or more flavouring agents or one or more mulated as a sterile injectable aqueous or oleaginous sus sweetening agents , such as sucrose , stevia , or saccharin . pension according to methods known in the art and using [ 0111 ] Pharmaceutical compositions can be formulated as one or more suitable dispersing or wetting agents and /or oily suspensions by suspending the active compound ( s ) in a suspending agents , such as those mentioned above . The vegetable oil , for example , arachis oil, olive oil , sesame oil sterile injectable preparation can be a sterile injectable or coconut oil , or in a mineral oil such as liquid paraffin . The solution or suspension in a non -toxic parentally acceptable oily suspensions may contain a thickening agent , for diluent or solvent, for example , as a solution in 1 , 3 -butane example , beeswax , hard paraffin or cetyl alcohol. Sweeten diol. Acceptable vehicles and solvents that can be employed ing agents such as those set forth above, and / or flavouring include , but are not limited to , water, Ringer' s solution , agents may be added to provide palatable oral preparations . lactated Ringer ' s solution and isotonic sodium chloride These compositions can be preserved by the addition of an solution . Other examples include , sterile , fixed oils , which anti -oxidant such as ascorbic acid . are conventionally employed as a solvent or suspending [0112 ] The pharmaceutical compositions can be formu medium , and a variety of bland fixed oils including , for lated as a dispersible powder or granules, which can subse example , synthetic mono - or diglycerides. Fatty acids such quently be used to prepare an aqueous suspension by the as oleic acid can also be used in the preparation of inject addition of water . Such dispersible powders or granules ables. provide the active ingredient in admixture with one ormore [0118 ] Due to the highly lipophilic nature of cannabinoids, dispersing or wetting agents , suspending agents and/ or pre these molecules are typically poorly absorbed through mem servatives. Suitable dispersing or wetting agents and sus branes such as the skin of mammals, including humans, and pending agents are exemplified by those already mentioned the success of transdermally administering therapeutically above . Additional excipients , for example , sweetening, fla effective quantities of cannabinoid to a subject in need vouring and colouring agents , can also be included in these thereof within a reasonable time frame and over a suitable compositions . surface area has been substantially limited . It is therefore 10113 ] Pharmaceutical compositions of the invention can proposed that the cannabinoid glycoside prodrugs of the also be formulated as oil - in -water emulsions . The oil phase present invention , through conjugation of the hydrophobic can be a vegetable oil, for example , olive oil or arachis oil, cannabinoid aglycone to the hydrophilic glycosidic moi or a mineral oil , for example , liquid paraffin , or it may be a eties , provide a molecule having an amphiphilic character mixture of these oils . Suitable emulsifying agents for inclu favourable for passive diffusion which should be more sion in these compositions include naturally -occurring readily absorbed through the skin . gums, for example , gum acacia or gum tragacanth ; natu [0119 ] Accordingly , in one embodiment, the pharmaceu rally -occurring phosphatides, for example , soy bean , leci tical compositions are formulated for topical administration . thin ; or esters or partial esters derived from fatty acids and Such topical formulations may be presented as, for example , hexitol, anhydrides , for example , sorbitan monoleate , and aerosol sprays , powders, sticks, granules, creams, liquid condensation products of the said partial esters with ethylene creams, pastes, gels , lotions , ointments , on sponges or cotton oxide, for example , polyoxyethylene sorbitan monoleate . applicators , or as a solution or a suspension in an aqueous The emulsions can also optionally contain sweetening and liquid , a non -aqueous liquid , an oil - in -water emulsion , or a flavouring agents . water - in - oil liquid emulsion . [0114 ] Pharmaceutical compositions can be formulated as [0120 ] Topical pharmaceutical compositions can be for a syrup or elixir by combining the active ingredient( s ) with mulated with thickening ( gelling ) agents . The thickening one or more sweetening agents , for example glycerol, pro agent used herein may include anionic polymers such as pylene glycol, sorbitol or sucrose . Such formulations can polyacrylic acid (CARBOPOL® by Noveon , Inc ., Cleve also optionally contain one or more demulcents , preserva land , Ohio ), carboxypolymethylene, carboxymethylcellu tives , flavouring agents and / or colouring agents . lose and the like , including derivatives of Carbopol® poly [ 0115 ] If desired , other active ingredients may be included mers , such as Carbopol® Ultrez 10 , Carbopol 940 , in the compositions . In one embodiment, the glycoside Carbopol 941, Carbopol 954 , Carbopol® 980 , Car prodrugs may be combined with other ingredients or sub bopol® 981, Carbopol® ETD 2001, Carbopol® EZ -2 and stances that have glycosidase activity, or that may in other Carbopol® EZ - 3 , and other polymers such as Pemulen® ways alter drug metabolism and pharmacokinetic profile of polymeric emulsifiers, and Noveon® polycarbophils . Thick various compounds in vivo, including ones in purified form ening agents or gelling agents are present in an amount as well as such compounds found within food , beverages , sufficient to provide the desired rheological properties of the and other products . In one embodiment, the cannabinoid composition . glycoside prodrug is administered in combination with , or [0121 ] Topical pharmaceutical compositions can be for formulated together with , substances that have direct gly mulated with a penetration enhancer. Non -limiting examples cosidase activity , or that contribute to modifications to the of penetration enhancing agents include C8 -C22 fatty acids gut microflora that will alter the glycosidase activity in one such as isostearic acid , octanoic acid , and oleic acid ; C8 - C22 or more regions of the intestines. Examples of such com fatty alcohols such as oleyl alcohol and lauryl alcohol; lower positions include , but are not limited to , yogurt, prebiotics , alkyl esters of C8 - C22 fatty acids such as ethyl oleate , probiotics, or fecal transplants . isopropyl myristate , butyl stearate , and methyl laurate ; [0116 ] In a further preferred embodiment, the pharmaceu di( lower )alkyl esters of C6 -C22 diacids such as diisopropyl tical compositions are formulated for parenteral administra adipate ; monoglycerides of C8 - C22 fatty acids such as tion . The term “ parenteral” as used herein includes subcu glyceryl monolaurate ; tetrahydrofurfuryl alcohol polyethyl US 2018 /0264122 A1 Sep . 20 , 2018 25 ene glycol ether ; polyethylene glycol, propylene glycol; [0129 ] In one embodiment, the one or more sugar donors 2 -( 2 - ethoxyethoxyl) ethanol; diethylene glycol monomethyl are selected from the group consisting of UDP - glucose , ether; alkylaryl ethers of polyethylene oxide ; polyethylene UDP - glucuronic acid , UDP -mannose , UDP - fructose, UDP oxide monomethyl ethers ; polyethylene oxide dimethyl xylose , UDP - rhamnose, UDP- fluoro - deoxyglucose, and ethers ; dimethyl sulfoxide ; glycerol; ethyl acetate ; combinations thereof. In a preferred embodiment, the sugar acetoacetic ester; N -alkylpyrrolidone ; and terpenes. donor is UDP - glucose . [0122 ] The topical pharmaceutical compositions can fur 10130 ] In accordance with the present invention , the can ther comprise wetting agents ( surfactants ) , lubricants , emol nabinoid aglycone is a cannabinoid , an endocannabinoid , or lients , antimicrobial preservatives, and emulsifying agents a vanilloid . In a preferred embodiment, the cannabinoid as are known in the art of pharmaceutical formations. glycoside prodrug produced by the methods of the present [ 0123 ] Transdermal delivery of the cannabinoid glycoside invention is a compound of the Formula (I ) . prodrug can be further facilitated through the use of a [ 0131 ] In one embodiment , the method of producing a microneedle array drug delivery system . cannabinoid glycoside comprises incubating a cannabinoid [0124 ] Other pharmaceutical compositions and methods aglycone with UDP - glucose, in the presence of a UGT76G1 of preparing pharmaceutical compositions are known in the or UGT76G1- like glucosyltransferase under conditions that art and are described , for example , in “ Remington : The allow for glycosylation . Science and Practice of Pharmacy ” ( formerly “ Remingtons [0132 ] In one embodiment, the method of producing a Pharmaceutical Sciences” ); Gennaro , A . , Lippincott, Wil cannabinoid glycoside comprises incubating a cannabinoid liams & Wilkins , Philadelphia , Pa . ( 2000 ) . aglycone with one or more sugar donors in the presence of [0125 ] The pharmaceutical compositions of the present a first glycosyltransferase and a second glycosyltransferase invention described above include one or more cannabinoid under conditions which allow for glycosylation . In one glycoside prodrugs of the invention in an amount effective embodiment, sugar donor is UDP - glucose , the first glyco to achieve the intended purpose . Thus the term “ therapeu syltransferase is a UGT76G1 or UGT76G1- like glucosyl tically effective dose ” refers to the amount of the cannabi transferase , and the second glycosyltransferase is a noid glycoside prodrug that improves the status of the Os03g0702000 or Os03g0702000 - like glucosyltransferase . subject to be treated , for example , by ameliorating the [0133 ] In one embodiment, the method of producing a symptoms of the disease or disorder to be treated , preventing cannabinoid glycoside comprises incubating a cannabinoid the disease or disorder, or altering the pathology of the aglycone with UDP - glucose in the presence of a UGT7661 disease . Determination of a therapeutically effective dose of or UGT76G1- like glucosyltransferase and Os03g0702000 a compound is well within the capability of those skilled in or Os03g0702000 - like glucosyltransferase under conditions the art. In one embodiment, cannabinoid glycosides can be which allow for glycosylation . combined to enable simultaneous delivery of multiple can [0134 ]. In one embodiment, the method of producing a nabinoids in a site - specific manner, including THC and cannabinoid glycoside comprises incubating a cannabinoid CBD , whose effects in some ways may be synergistic (Russo aglycone with maltodextrin , in the presence of a cyclodex 2006 ) . Accordingly, in one embodiment, the pharmaceutical trin glucanotransferase under conditions that allow for gly composition comprises one or more CBD -glycosides and cosylation . one ormore THC - glycosides formulated together in a single [0135 ] In one embodiment, the method of producing a dosage form . cannabinoid glycoside comprises incubating a cannabinoid 10126 ]. The exact dosage to be administered to a subject aglycone with UDP - glucose and maltodextrin in the pres can be determined by the practitioner, in light of factors ence of a UGT76G1 or UGT76G1- like glucosyltransferase related to the subject requiring treatment. Dosage and and cyclodextrin glucanotransferase under conditions which administration are adjusted to provide desired levels of the allow for glycosylation . cannabinoid glycoside prodrug and / or the cannabinoid drug [0136 ] In a preferred embodiment, the glycosyltransferase compound obtained upon hydrolysis of the prodrug . Factors employed in the methods of producing the cannabinoid which may be taken into account when determining an glycoside is UGT76G1 or UGT76G1- like glucosyltrans appropriate dosage include the severity of the disease state , ferase . In one embodiment, the UGT76G1 or UGT76G1- like general health of the subject, age , weight, and gender of the glucosyltransferase comprises the sequence as set forth in subject, diet , time and frequency of administration , drug SEQ ID NO : 1 , 3 , 5 or 7 . combination ( s ) , reaction sensitivities, and tolerance / re [0137 ] In one embodiment, the glycosyltransferase sponse to therapy . Dosing regimens can be designed by the employed in the methods of producing the cannabinoid practitioner depending on the above factors as well as glycoside is Os03g0702000 or Os03g0702000 - like gluco factors such as the half - life and clearance rate of the par syltransferase . In one embodiment, the Os03g0702000 or ticular formulation . Os03g0702000 - like glucosyltransferase comprises the 101271. In accordance with the present invention , there is sequence as set forth in SEQ ID NO : 9 . provided a method of producing a cannabinoid glycoside , [0138 ] In one embodiment , the method of producing the comprising incubating a cannabinoid aglycone with one or cannabinoid glycoside further comprises incubating with more sugar donors in the presence of one or more glyco sucrose synthase . In one embodiment, the sucrose synthase syltransferases. comprises the sequence as set forth in SEQ ID NO : 15 , 17 , [0128 ]. In one embodiment, the one or more glycosyltrans 19 , 21, 23 or 25 . ferases is a UGT76G1 or UGT76G1- like glucosyltrans [0139 ] In one embodiment, the method for the production ferase . In one embodiment , the one or more glycosyltrans of a cannabinoid glycoside prodrug comprises expressing ferases comprise a UGT76G1 or UGT76G1- like one or more of the glycosyltransferases in a cell or plant glucosyltransferase and a Os03g0702000 or Os03g0702000 which produces the cannabinoid aglycone and isolating the like glucosyltransferase . cannabinoid glycoside prodrug . US 2018 /0264122 A1 Sep . 20 , 2018 26

[0140 ] Glycosylation of cannabinoids improves solubility optimization was performed (SEQ ID NOs. 4 and 6 ) for in aqueous solutions , as demonstrated by accelerated elution expression in Pichia pastoris . Similar to its activity towards from an C18 analytical HPLC column , indicating that the steviol glycosides, UGT76G1 is highly productive and has new cannabinoid - glycosides require far less organic solvent an equilibrium constant (Keq ) for CBD of ~ 24 . Through for elution from the hydrophobic chromatography column . experimentation and analysis it was determined that This improved solubility was further demonstrated by test UGT76G1 has the unique ability to apply multiple glucose ing the aqueous solubility of purified solid cannabosides , moieties to the CBD molecule . Upon prolonged incubation where solutions were successfully prepared up to 500 mg/ ml of CBD with UGT76G1 and UDPG , HPLC analysis of the (50 % mass/ volume) with a mixture of higher glycoside forms of cannabosides . Given the markedly improved solu reaction mixture yielded 8 glycoside product mobility bility and novel secondary and tertiary glycosylation on groups , suggesting that UGT761 is able to glycosylate cannabinoids, glycosylated cannabinoids can act as efficient both the C2 ' and C6 ' hydroxyl groups on CBD , as well as prodrugs for selective delivery of cannabinoids to desired glycosylating the primary glucose residues with a secondary tissues where the glucose molecules can be hydrolyzed to and tertiary glucose moieties. The secondary and tertiary release the aglycone cannabinoids . Additionally the glyco glycosylations by UGT76G1 occurs at the C3 hydroxyl sylations promote stability of CBD and CBDV by protecting group of the recipient sugar ( 3 - > 1 connectivity ) , as would be them from oxidation and ring - closure of the C6 -hydroxyl suggested by its activity in Stevia , creating O -( 3 - 1 ) - glyco group , which prevents degradation into A9 - THC or sides, and the subsequent products . The CBD - glycoside A9 - THCV, respectively , and subsequently into cannabinol product mobility groups also suggest that CBD can dock in (CBN ) or cannabinavarin (CBNV ) , respectively the UGT76G1 active site both forwards and backwards [0141 ] Increasing the diversity and complexity of sugar creating a cis - like - conformation for the glycosylations rela attachments to cannabinoids, and administration of a mix tive to the cannabinoid backbone (mechanism depicted in ture of glycosides will provide altered prodrug delivery FIG . 3 ) , or possibly the rotational freedom about the bond at kinetics, thus providing an extended release formulation of Cl' (C6 described by Mazur 2009) allows the hydroxyl the drug . The primary detoxification mechanism for can group to rotate after glycosylation , placing the other nabinoids in humans is CYP450 mediated hydroxylation of hydroxyl group adjacent to the UDPG in the active site and the C7 methyl group of CBD and CBDV, or the C11 methyl creating a trans - like- conformation for the glycosylations on group of THC and CBN , glycosylation of the acceptor the cannabinoid backbone (mechanism depicted in FIG . 4 ). hydroxyl groups of the cannabinoid resorcinol ring may Potential CBD molecular docking in the active site of afford protection from C7 /C11 hydroxylation and subse UGT76G1 is depicted in FIG . 6 where CBD is superposi quent elimination from the body due to steric hindrance tioned over the bi- functional substrate for UGT76G1, preventing the cannabinoid - glycoside from binding in the Rebaudioside E (RebE ) (FIG . 6 ) CYP450 active site . In fact, the hydroxyl groups of CBD are thought to facilitate the binding to the detoxification [0143 ] As CBD was successfully glycosylated by cytochrome P450 CYP3A4 in the epithelium of the small UGT76G1, CBDV was incubated with UGT76G1 and intestine ( Yamaori 2011 ) . Reduced degradation or metabo UDPG to test for glycosylation activity . CBDV depletion lism in the stomach and small intestine due to these effects was observed upon HPLC analysis , in addition to the could also lead to higher total bioavailability of any glyco appearance of four additional product peak mobility groups , sylated product upon oral delivery . which were dependent on addition of both UGT76G1 and UDPG . The four new products formed displayed the same [ 0142 ] In some cases, removal of the sugar from glyco absorbance characteristics as CDBV and were determined to sides in the body may be required in order for the com be the primary glycosides CBDV -2 - 0 - glucopyranosides, pounds to exert their primary biological activity . Therefore , CBDV - 6 - O - glucopyranosides, and the secondary glyco glycoside prodrugs may enable stable drug formulations that sides CBDV - 2 - 0 - ( 3 - 1 ) - diglucopyranoside, and CBDV - 6 are resistant to abuse , due to the potential for their primary biological effects to only occur after oral ingestion . As most O -( 3 - 1 )- diglucopyranoside (compounds VB202 , VB206 , abuse -deterrent compounds are simply mixing or formula VB204 and VB208 , respectively , Table 2 ) . With additional tion based deterrents , they can still be compromised by reaction time it was determined that higher order glycoside simple physical and chemicalmethods . As one example , the products were also formed . CBDV - glycoside production beta - glycosides described herein will only release the agly was similar to CBD - glycosides from UGT76G1 ( Table 2 ) , cone upon the action of beta -glycosidase enzymes . Beta and proceeded to completion with a Keg ~ 24 . Given the glycosidases are known to be secreted by microbes that number of CBDV - glycoside products , UGT76G1 transfers occupy the large intestines ofmammals , therefore upon oral multiple glucose molecules onto CBDV on both C2' and C6 ingestion the glycoside prodrugs will remain glycosylated hydroxyl groups, as well as onto the primary and secondary until they reach the large intestine . A similar approach may glycosylations. be used for abuse - resistant, abuse -deterrent , and site - specific [0144 ] When the cannabinoid A9 - THC was incubated delivery of other compounds through glycosylation . It has with UGT76G1 and UDPG , HPLC analysis of the reaction been found that the UGT76G1 enzyme ( SEQ ID NO . 1 ) from mixture showed three main product peak mobility groups . Stevia rebaudiana transfers a glucose molecule from the The three products were identified as A9 - THC - 1- 0 -glucopy sugar donor UDP - glucose (UDPG ) to the hydroxyl groups ranoside , A9 - THC - 1 - 0 - ( 3 - 1 ) - diglucopyranoside , and of CBD to create novel CBD - O -glycosides ( Table 1 , FIGS. A9 - THC - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside ( formal pyran 2 & 4 ) . The UDPG is inverted by UGT76G1 to produce numbering, Table 3 , FIG . 7 ) . Given that the rigid structure B - D - glucose residues covalently linked through the to the of A9 - THC does not have the same rotational freedom as hydroxyl acceptor sites on CBD . To improve the catalytic CBD around the Cl' resorcinol ring attachment, the can efficiency UGT76G1 open reading frame (ORF ) codon nabinoid backbone is recognized in the active site of US 2018 /0264122 A1 Sep . 20 , 2018 27

UGT76G1 with the A9- THC C1 hydroxyl group situated SDFGLDQ ( AA ' s 375 to 381 of UGT76G1) . Suitable towards the UDPG sugar donor ( pyran numbering, FIG . enzymes for producing the secondary glycosylation of 1B ) . Os03g0702000 are members of the UGT91 clade, including [0145 ] As UGT76G1 demonstrated glycosylation activity UGT91 D1 and UGT91 D2. for all other phytocannabinoids analyzed , it was also tested [0150 ] The glycosylation reactions performed herein for glycosylation activity against cannabinol (CBN ) . Effec included UDP -glucose as the nucleotide sugar donor, how tive glycosylation of CBN by UGT76G1 was observed , in a ever there is some cross - reactivity amongst UGTs that similar pattern to A9 - THC , as both share a single hydroxyl allows for use of alternative nucleotide sugars such as recipient group at the C1 position of the resorcinol ring. The UDP - glucuronic acid , etc . Glucuronic acid is the predomi activity seen with UGT76G1 is consistent with a broad nant nucleotide sugar utilized by phase - II detoxification recognition of cannabinoids by the enzyme active site . UGTs in the liver , and cannabinoid - glucuronides are a 10146 ]. Alternative cannabinoid substrates may be inserted common detoxification product. Additional nucleotide sug into this UGT76G1 glycosylation reaction infrastructure to ars which could be used to donate carbohydrate moieties to generate novel cannabinoid - glycosides, given they possess create novel glycosides with similar properties include hydroxyl groups in similar positions on the cannabinoid UDP - glucuronic acid , UDP -mannose , UDP - fructose , UDP backbone . Ideal candidates are cannabigerol (CBG ) , can xylose , UDP -rhamnose , UDP - fluorodeoxyglucose , etc . In nabichromene (CBC ) , cannabidiol hydroxyquinone (CB addition , nucleotide sugars can also be used in combination DHQ ) , HU -331 , other isomers of A9 - THC such as A8 - THC , to create glycosides that contain multiple types of residues etc ., and synthetic analogues of A9 - THC such as HU -210 . on the same aglycone backbone . Alternative strategies to [0147 ] Similar to the secondary 3 - 1 glycosylation activ further improve the solubility and delivery of cannabinoids ity of UGT76G1, it was determined that following a primary and other compounds described herein include their glyco glycosylation by UGT76G1, the UGT enzyme sylation and then functionalizing the sugar moieties with Os03g0702000 (SEQ ID NO . 9 ) from Oryza sativa is also additional ligands or modifications. Examples of this include capable of transferring an additional glucose moiety from sulfation , myristoylation , phosphorylation , acetylation , etc . UDP -glucose onto the C2 -hydroxyl of the primary sugar [0151 ] The endocannabinoid system has recently been the ( Tables 1 - 11, FIGS. 7 - 9 & 12 - 14 ) . This glycosylation activ subject of intense research efforts due to its demonstrated ity is consistent with the activity of UGT Os03g0702000 role in and impact on a broad range of clinical pathologies . towards steviol glycosides in establishing C2 -hydroxyl sec As UGT76G1 has been determined to recognize a broad ondary glycosylations ( 2 - > 1 connectivity ) on existing pri class of phytocannabinoids, it was hypothesized that the mary glucose residues . This secondary glycosylation was same enzyme would also recognize and glycosylate endo observed with CBDV ( Table 2 , FIG . 3 ), and THC ( Table 2 , cannabinoids , which are the endogenous signaling mol FIG . 7) , generating novel CBDV and ASTHC -1 - 0 -( 2 - 1 ) ecules recognized by the cannabinoid receptors in Humans. diglucopyranoside species , respectively . Consistent with Upon testing a sample of four prototypic endocannabinoids broad substrate recognition and reactivity , this activity of including arachidonoylethanolamide (anandamide , AEA ) , Os03g0702000 was further demonstrated for the remainder 2 -arachidonoylethanolamide (2 - AG ), 1- arachidonoyletha of the substrates identified in FIG . 1 . nolamide ( 1 - AG ) , and docosahexaenoyl ethanolamide [0148 ] In addition to the UDPG -dependent glucosyltrans (DHEA , synaptamide ) , it was found that UGT76G1 effec ferase activity , cyclodextrin - glucanotransferase (CGTase , tively glycosylated each endocannabinoid ( Tables 5 - 8 , Toruzyme 3 .0L , trademark of Novozymes Inc. ) is capable of FIGS . 9 - 12 ) . Glycosylation of endocannabinoids enables the transferring a short a - ( 1 - 4 ) - maltodextrin chain onto the creation of endocannabinoid - glycosides and other fatty acid hydroxyl groups of cannabinoids . The CGTase is also neurotransmitter- glycosides , representing a new method of capable of glycosylating primary and secondary glycosy targeted delivery of endocannabinoids . lations established by UGT76G1 and Os03g0702000 , result [0152 ] As endocannabinoids such as AEA , 2 -AG , 1 - AG , ing in carbohydrate attachments that start with B - D - glucose and synaptamide are glycosylated by UGT76G1, it is molecules , but terminating in a - D - glucose molecules hypothesized that similar endocannabinoids will also be termed B -primed - a -glucosyl ( Tables 1- 11) . a - glycosylation suitable substrates for glycosylation by UGT76G1. Other by cyclodextrin glucanotransferase mediated maltodextrin endocannabinoid candidates that are likely to be glycosy transfer can occur on any of the hydroxyl groups of the lated by UGT76G1 include oleoyl ethanolamide (OEA ), primary or secondary sugars covalently linked to the can eicsapentaenoyl ethanolamide , prostaglandin ethanolamide, nabinoid . One skilled in the art will appreciate that this docosahexaenoyl ethanolamide, linolenoyl ethanolamide , makes possible any number of conformations of a - glycosyl 5 ( 2 ) , 8 ( Z ) , 11 ( Z ) - eicosatrienoic acid ethanolamide (mead chains linked to the glycosides listed in Tables 1 - 11 . acid ethanolamide ) , heptadecanoul ethanolamide , stearoyl [0149 ] Alternative enzymes with homology to UGT7661 ethanolamide , docosaenoyl ethanolamide , nervonoyl etha and Os03g0702000 may be used to produce the same nolamide, tricosanoyl ethanolamide , lignoceroyl ethanol glycosylation of cannabinoids . Suitable enzymes for estab amide , myristoyl ethanolamide , pentadecanoyl ethanol lishing the primary glycosylation similar to UGT76G1 are amide , palmitoleoyl ethanolamide , docosahexaenoic acid additionalmembers of the UGT76 clade such as UGT76G2 (DHA ) , and similar compounds. These glycolipids may have or UGT76H1. BLAST results with the UGT76G1 protein a wide range of commercial uses , ranging from pharmaceu sequence yield a maximum homology of 49 % identity , as tical use as a novel endocannabinoid drug with improved much as 66 % positives ( similar identity ) . Ideal candidates solubility and pharmacokinetic properties, to use as an may have low overall peptide identity or similarity , but will antibacterial agent, to use as a detergent similar to other likely have conserved amino acids at the opening adjacent to glycolipids, etc . the UDPG catalytic site . This sequence is exemplified by a [0153 ] It has been characterized that AEA and CBD are leucine at position 379 , and a broader peptide sequence of full agonists of the toll- like vanilloid receptor type 1 US 2018 /0264122 A1 Sep . 20 , 2018

( TRPV1 ), which is the receptor for capsaicin . In addition , other compounds described herein may benefit from other cannabinoids and botanical extracts , including but not enhanced facilitated transport across the BBB or other limited to CBD , CBN , cannabigerol (CBG ) , and various barriers . Glucose transporters are a wide group ofmembrane propyl homologues of CBD , THC , and CBG have been proteins encoded by the human genome and that are found demonstrated to bind and have activity towards transient not only in the BBB but across many different cells and receptor potential channels ( TRPs ) (De Petrocellis 2011 ) . tissues , including brain , erythrocytes , fat, muscle , kidney , This includes stimulating and desensitizing TRPV1, as well liver , intestine , and pancreas , so glycosylation will be tai as TRPA1, TRPV2, and also antagonism of TRPM8. lored to provide site -specific delivery to any of these tissues . Although stimulation of TRPV1 leads to vasodilation and Accordingly , in one embodiment, there is provided a method inflammation , capsaicin and its analogues act to desensitize for facilitating the transport of a cannabinoid drug across the the receptors to stimulants, and provide potent anti - inflam blood brain barrier of a subject comprising administering to matory effects (Bisogno 2001) . Analogous effects may occur the subject a cannabinoid glycoside prodrug in accordance with TRPA1 in addition to other TRPs. For CBD , this may with the present invention . occur at concentrations that are lower than what is required [0156 ] Delivery of cannabinoids and cannabidiol to the for binding of cannabinoid receptors , and at concentrations brain may be especially useful because of oligodendrocyte that are within the range of those typically attained in human protective ( oligoprotective ) and general neuroprotective clinical testing and use. In addition to acting as a direct effects. It has been demonstrated that cannabinoid signaling agonist of the TRPV1 receptor, CBD has been shown to is involved with both oligodendrocyte differentiation inhibit fatty acid amide hydroxylase (FAAH ) , the enzyme (Gomez 2010 ) and that cannabinoids promote oligodendro responsible for facilitating the metabolism of the endocan cyte progenitor survival (Molina -Holgado 2002 ) . Drug for nabinoid anandamide (Watanabe , 1998 ; DE e Petrocellis mulations that include cannabidiol as a major ingredient 2010 ) . Given that these phytocannabinoids act as ligands of have been approved to treat muscle spasticity and pain from diverse TRPs , it was postulated that UGT76G1 would be multiple sclerosis , a neurodegenerative disorder that causes capable of glycosylating many different ligands of the same loss of myelin and oligodendrocyte progenitor cells . The TRPs, including TRPM8, TRPV2, TRPA1, and TRPV1. effects of cannabidiol have been demonstrated to mediate Capsaicin is capable of contorting into a CBD - like structure oligoprotective effects through attenuation of endoplasmic (Bisogno 2001) , therefore it was postulated that capsaicin reticulum stress pathways (Mecha 2012 ) . Cannabidiol has was likely to be a suitable substrate for glycosylation by also been studied extensively for its antipsychotic effects , UGT76G1. To this end , it was shown that UGT76G1 is however the exact role in protection of oligodendroctyes and capable of glycosylating the vanilloid moiety of capsaicin in promotion of remyelination has not yet been described a structurally identical way to PaGT3 from Phytolacca ( Zuardi 2012 ) . Despite the correlation between the clinical americana ( Noguchi 2009 ) . As the glycosylated structure of symptoms of psychosis with neuropathological analysis that capsaicin is the vanilloid head , it was further hypothesized indicates dysmyelination is involved , the role of dysmyeli that UGT76G1 would be capable of glycosylation of the nation as a driver or cause of schizophrenia and other minimal vanilloid , i . e . , vanillin , as well as many analogues . psychoses remains controversial (Mighdoll 2015 ) . Remyeli Consistent with this hypothesis , through HPLC analysis it nation has also been described as potentially useful for was determined that UGT76G1 created multiple glycoside treatment of Alzheimer ' s disease and other forms of demen products of vanillin ( FIG . 14 , Table 10 ) . Seeking to test the tia (Bartzokis 2004 ) . Therefore , delivery of cannabinoids to ability of UGT76G1 to glycosylate vanilloids more broadly , the brain may be especially useful for its established neu curcumin , the well characterized vanilloid found in turmeric roprotective and oligoprotective effects . Cannabinoid gly spice , isolated from the ginger Curcuma longa was applied coside drug formulations co - administered in combination as a substrate in the glycosylation reaction . Consistent with with other agents that influence other aspects of repair or the glycosylation of vanillin , UGT76G1 effectively glyco regeneration , such as oligodendrocyte progenitor differen sylated curcumin , creating multiple glycoside product tiation or remyelination , may also prove to be beneficial . peaks , suggesting a bifunctional recognition and glycosy This includes compounds such as anti- LINGO - 1 monoclo lation by UGT76G1 similar to that seen with CBD and nal antibodies , guanabenz , sephinl, benzatropine, clemas steviol glycosides ( FIGS. 15A & 15B , Table 11) . tine , polyunsaturated fatty acids , etc . [0154 ] Cannabinoid glycosides may also have direct bio [ 0157 ] In the course of the present work , it was discovered active and therapeutic effects , beyond their utility a prodrug that UGT76G1, 050390702000 and cyclodextrin glucano for their aglycone form . Quercetin is an antioxidant fla transferase (CGTase ) were capable of primary , secondary vonoid that is ubiquitous in vegetables and often present and tertiary glycosylations of steviol glycosides and agly both in its aglyone and glycosylated forms. It has been cone products of diverse chemical structure , including can demonstrated through in vitro studies that quercetin glu nabinoids, endocannabinoids , vanillin , curcumin , and cap curonides act as a bioactive agent as well as a precursor saicin . molecule to aglycone quercetin ( Terao 2011 ) . In many cases , [0158 ] In the screening and analysis methods described by including with glycosides that exert antibacterial and anti Dewitte 2016 , a 50 mm HPLC separation column combined tumor effects, the glycosidic residues are crucial to activity with a high solvent flow rate was used limiting the separa ( Kren & Rezanka 2008 ). tion and overall detection of glycoside products . Thus, the [ 0155 ] Glycosides have also been demonstrated to receive interpretation of the glycosylation reaction products for facilitated transport across the blood brain barrier (BBB ) by many compounds is speculative , yet still reinforces the the glucose transporter GLUT1. A prime example is the significance of the present finding that UGT76G1 has broad glycoside of ibuprofen achieving a significant increase of substrate specificity . Clearly , the work described herein ibuprofen aglycone concentration in the brain (Chen 2009 ) . demonstrate that UGT76G1 can glycosylate not only steviol Similar to these glycosides , glycosides of cannabinoids and glycosides, but other forms of glycosides , and novel agly US 2018 /0264122 A1 Sep . 20 , 2018 cone compounds such as cannabidiol as well . Internal stud capable of primary , secondary , tertiary glycosylations or a ies that used an improved separation methodology involving combination thereof. In certain embodiments , the glycosyl a 150 mm length C18 column coupled with a low solvent transferases are capable of primary , secondary and tertiary flowrate also enabled the clear detection of secondary and glycosylations . In other embodiments , the glycosyltrans tertiary glycosides . These compounds were unable to be ferases are capable of secondary and tertiary glycosylations . detected by the methods described in Dewitte 2016 , and In certain embodiments , the nucleic acids encode a gluco provide additional verification of the ability of UGT76G1 to syltransferase , including but not limited to a UDP - glucosyl not only glycosylate compounds with diverse chemical transferase . The glucosyltransferases include but are not structures, but also to perform multiple higher order glyco limited to a Stevia rebaudiana UDP- glucosyltransferase , sylations on glycosides of these same compounds . such as UGT76G1 or UGT74G1 or an Oryza sativa gluco [0159 ] The reactions described herein take place in vitro syltrasferase, such as Os03g0702000 . In other embodiments , using recombinant enzymes and all necessary cofactors, and the invention provides for nucleic acids comprising nucleo the expression of UGT76G1 enzyme within the cells of a tide sequences encoding a cyclodextrin glucanotransferase . Cannabis plant is possible for the in vivo biotransformation Also provided are nucleic acids comprising nucleotide of cannabinoids prior to extraction of cannabinoids from sequences that encode a sucrose synthase . plant tissue . As UGT76G1 is an enzyme from the plant [0163 ] Nucleic acids include , but are not limited to , Stevia rebaudiana , it will be compatible with expression in genomic DNA , cDNA , RNA , fragments and modified ver the genus Cannabis . The ideal strategy for expression of sions , including but not limited to codon optimized versions UGT76G1 within the Cannabis plant is to genetically engi thereof. For example , the nucleotide sequences may be neer the UGT76G1 open reading frame under a promoter codon optimized for expression in Pichia pastoris or E . coli . element that is specific for the same tissue that cannabinoids The nucleic acids may include the coding sequence of the are produced in , namely the secretory trichomes of the plant. glycosyltransferase or sucrose synthase , in isolation , in Suitable promoter elements include the promoter for the cytosolic O - acetylserine ( thiol) lyase (OASA1 ) enzyme from combination with additional coding sequences ( e . g . , includ Arabidopsis thaliana (Gutierrez - Alcala 2005 ) . Candidates ing but not limited to a purification tag ) . for transformation with UGT76G1 include Cannabis sativa , [0164 ] In certain embodiments , the nucleic acid comprises Cannabis indica , and Cannabis ruderalis . A similar a sequence encoding UGT76G1 or UGT76G1- like gluco approach may be used with UGT76G1 and similar enzymes syltransferase . UGT76G1- like glucosyltransferase include for in planta production of glycosylated secondary metabo for example, other members of the UGT76G1 clade such as lites within many other different plant species , and may be UGT76G2 or UGT76H1. In certain embodiments , the especially useful when plant species already produce large nucleic acid comprises a sequence encoding an UGT76G1 quantities of the desired aglycone product or known enzyme glucosyltransferase having the amino acid sequence as set substrate . forth in any one of SEQ ID NOs: 1 , 3 , 5 and 7 and listed [0160 ] In the course of performing phytocannabinoid gly below or fragments and variants thereof. cosylation reactions CBD and THC displayed noticeable antimicrobial activity , even preventing large -scale reaction ( UGT 76G1 ( native protein sequence ) ) mixtures from becoming contaminated after failure of the SEQ ID NO : 1 sterile filter apparatus. Prior pilot- scale glycosylation reac MENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKGFSITIFHTNF tion utilizing steviol glycosides as substrates during enzy matic processing were quite susceptible to infection in the NKPKTSNYPHFTFRFILDNDPODERISNLPTHGPLAGMRIPIINEHGADE absence of strict sanitation techniques . CBD and THC LRRELELLMLASEEDEEVSCLITDALWYFAQSVADSLNLRRLVLMTSSLF pilot - scale reactions remained aseptic for over a week in the same reaction vessels with very limited ongoing mainte NFHAHVSLPQFDELGYLDPDDKTRLEEQASGFPMLKVKDIKSAYSNWQIL nance or care . To this end , the use of the aglycone cannabi noids and their respective glycosides is proposed as efficient KEILGKMIKOTKASSGVIWNSFKELEES ELETVIREIPAPSFLIPLPKHL antimicrobial agents . Accordingly , in one embodiment, there TASSSSLLDHDRTVFQWLDOQPPSSVLYVSFGSTSEVDEKDFLEIARGLV is provided an antimicrobial agent comprising an effective amount of a cannabinoid glycoside prodrug in accordance DSKOSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWVPQQEVLAHGAI with the present invention . GAFWTHSGWNSTLESVCEGVPMIFSDFGLDQPLNARYMSDVLKVGVYLEN [0161 ] Similarly , upon the production of large quantities of cannabinoid - glycosides and formulation in aqueous solu GWERGEIANAIRRVMVDEEGEYIRQNARVLKQKADVSLMKGGSSYESLES tions , it was observed that multiple cannabinoid - glycosides in water had foaming properties similar to detergents . This LVSYISSL is consistent with other glycoside detergents like 8 -octyl ( UGT 76G1 with a 6x Histidine tag at the glycoside, 8 -octylthioglycoside , and similar , and establishes N - terminus ) a potential use for cannabinoid - glycosides as a detergent. SEQ ID NO : 3 Accordingly , in one embodiment, there is provided a deter MHHHHHHGSGENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKGF sive agent comprising an effective amount of a cannabinoid SITIFHTNFNKPKTSNYPHFTFRFILDNDPODERISNLPTHGPLAGMRIP glycoside prodrug in accordance with the present invention . IINEHGADELRRELELLMLASEEDEEVSCLITDALWYFAOSVADSLNLRR Nucleic Acids LVLMTSSLFNFHAHVSLPQFDELGYLDPDDKTRLEEQASGFPMLKVKDIK [0162 ] The present invention provides for nucleic acids comprising nucleotide sequences encoding a glycosyltrans SAYSNWQILKEILGKMIKOTKASSGVIWNSFKELEESELETVIREIPAPS ferase . The glycosyltransferases of the present invention are US 2018 /0264122 A1 Sep . 20 , 2018 30

- continued - continued FLIPLPKHLTASSSSLLDHDRTVFOWLDOOPPSSVLYVSFGSTSEVDEKD CGCTCGCTGGTATGCGGATTccGATTATCAACGAACACGGAGCTGACGAA FLEIARGLVDSKOSFLWVVRPGFVKGS TWVEPLPDGFLGERGRIVKWVPQ TTACGACGCGAACTGGAACTGTTGATGTTAGCTTCTGAAGAAGATGAAGA OEVLAHGAIGAFWTHSGWNSTLESVCEGVPMIFSDFGLDOPLNARYMSDV GGTATCGTGTTTAATCACGGATGc???TTGGTACTICGCGCAATCTGTTG LKVGVYLENGWERGEIANAIRRVMVDEEGEYIRONARVLKOKADVSLMKG CTGACAGTCTTAACCTCCGACGGCTTGTTTTGATGACAAGCAGCTTGTTT GSSYESLESLVSYISSL AATTTTCATGCACATGTTTC????ccTCAGTTTGATGAGCTIGGTTACCT ( UGT76G1 with a 6x Histidine -Glutamine tag at the N - terminus ) CGATCCTGATGACAAAACCCGTTTGGAAGAACAAGCGAGTGGGTTTCCTA SEQ ID NO : 5 MHQHQHQSGSMENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKG TGCTAAAAGTGAAAGACATCAAGTCTGCGTATTCGAACTGGCAAATACTC FSITIFHTNFNKPKTSNYPHFTFRFILDND PODERISNLPTHGPLAGMRI AAAGAGATATTAGGGAAGATGATAAAACAAACAAGAGCATCTTCAGGAGT PIINEHGADELRRELELLMLASEEDEEVSCLITDALWYFAQSVADSLNLR CATCTGGAACTCATTTAAGGAACTCGAAGAGTCTGAGCTCGAAACTGTTA RLVLMTSSLFNFHAHVSLPQFDELGYLDPDDKTRLEEQASGFPMLKVKDI TCCGTGAGATCCCGGCTCCAAGTTTCTTGATACCACTCCCCAAGCATTTG KSAYSNWQILKEILGKMIKOTKASSGVIWNSFKELEESELETVIREIPAP ACAGCCTCTTCCAGCAGCTTACTAGACCACGATCGAACCGTTTTTCAATG SFLIPLPKHLTASSSSLLDHDRTVFQWLDOQPPSSVLYVSFGSTSEVDEK GTTAGACCAACAACCGCCAAGTTCGGTACTGTATGTTAGTTTTGGTAGTA DFLEIARGLVDSKOSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWP CTAGTGAAGTGGATGAGAAAGATTTCTTGGAAATAGCTCGTGGGTTGGTT QQEVLAHGAIGAFWTHSGWNSTLESVCEGVPMIFSDFGLDQPLNARYMSD GATAGCAAGCAGTCGTTTTTATGGGTGGTTCGACCTGGGTTTGTCAAGGG VLKVGVYLENGWERGEIANAIRRVMVDEEGEYIRONARVLKOKADVSLMK TTCGACGTGGGTCGAACCGTTGCCAGATGGGTTCTTGGGTGAAAGAGGAC GGSSYESLESLVSYISSL GTATTGTGAAATGGGTTCCACAGCAAGAAGTGCTAGCTCATGGAGCAATA SEO ID NO : 7 GGCGCAT???GGACTCATAGCGGATGGAACTCTACGTTGGAAAGCGTTTG MENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKGFSITIFHTNF TGAAGGTGTTccTATGATTTTCTCGGATTTTGGGCTCGATCAACCGTTGA NKPKTSNYPHFTFRFILDNDPODERISNLPTHGPLAGMRIPIINEHGADE ATGCTAGATACATGAGTGATGTTTTGAAGGTAGGGGTGTATTTGGAAAAT LRRELELLMLASEEDEEVSCLITDALWYFAQSVADSLNLRRLVLMTSSLF GGGTGGGAAAGAGGAGAGATAGCAAATGCAATAAGAAGAGTTATGGTGGA NFHAHVSLPQFDELGYLDPDDKTRLEEQASGFPMLKVKDIKSAYSNWQIL TGAAGAAGGAGAATACATTAGACAGAATGCAAGAGTTTTGAAACAAAAGG KEILGKMIKOTRASSGVIWNSFKELEESELETVIREIPAPSFLIPLPKHL CAGATGTTTCTTTGATGAAGGGTGGTTCGTCTTACGAATCATTAGAGTCT TASSSSLLDHDRTVFQWLDOQPPSSVLYVSFGSTSEVDEKDFLEIARGLV CTAGTTTCTTACATTTCATCGTTGTAA DSKOSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWVPQQEVLAHGAI ( Sequence encoding SEQ ID NO : 3 codon optimized GAFWTHSGWNSTLESVCEGVPMIFSDFGLDQPLNARYMSDVLKVGVYLEN for expression in Pichia pastoris ) SEQ ID NO : 4 GWERGEIANAIRRVMVDEEGEYIRQNARVLKQKADVSLMKGGSSYESLES ATGCACCACCATCACCACCATGGTTCTGGTGAAAACAAAACTGAAACTAC LVSYISSLGSHHHHHH TGTTAGAAGAAGAAGAAGAATCATTTTGTTTCCAGTACCATTTCAAGGCC [ 0165 ] In certain embodiments , the nucleic acid comprises ATATCAATCCAATTCTTCAATTGGCCAATGTTTTGTACTCCAAAGGATTC a sequence encoding UGT76G1 having the amino acid TCCATCACCATTTTTCACACCAATTTCAACAAACCAAAGACTTCCAACTA sequence as set forth in AAR06912 .1 . In certain embodi ments , the nucleic acid molecule comprises a sequence TCCTCACTTCACTTTCAGATTTATTTTGGATAATGATCCTCAAGATGAAA enencoding UGT76G1 glucosyltransferase and comprising the GAATT?????????ccGACTCATGGTCCTTIGGCTGGTATGAGAATTccA nucleotide sequence as set forth in any one of SEQ ID NOs: 2 , 4 , 6 and 8 and listed below , or fragments and variants ATCATCAATGAACATGGTGCTGATGAATTAAGAAGAGAATTGGAACTTTT thereof. GATGTTGGCTTCTGAAGAAGATGAAGAAGTTTCATGTTTAATCACTGATG CTTTATGGTATTTTGCTCAATCTGTTGCTGATTCTTTGAATTTGCGACGG ( UGT 76G1 native nucleic acid sequence ) SEQ ID NO : 2 TTGGTTTTGATG????c??cTTTGTICAACTTTCATGCTCATGTTTc??? ATGGAAAATAAAACGGAGACCACCGTTCGCCGGCGCCGGAGAATAATATT ACCTCAGTTTGATGAACTTGGATATTTGGATCCAGATGACAAAACTAGAT ATTCCCGGTACCATTTCAAGGCCACATTAACCCAATTCTTCAGCTAGCCA TGGAAGAACAAGCTAGTGGGTTTCCTATGTTGAAAGTCAAAGATATCAAA ATGTGTTGTACTCTAAAGGATTCAGTATCACCATCTTTCACACCAACTTC TCTGCTTACTCCAACTGGCAAATTCTCAAAGAAATTTTGGGAAAAATGAT AACAAACCCAAAACATCTAATTACC?????????????CAGATTCAT??? CAAACAAACAAAAGCTTCTTCTGGAGTCATTTGGAACTCATTCAAAGAAT CGACAACGAccCACAAGACGAACGCATTTcCAATCTACCGACTCATGGTC US 2018 /0264122 A1 Sep . 20 , 2018

- continued - continued TGGAAGAATCTGAATTGGAAACTGTTATTAGAGAAATTCCTGCTCCAAGT TTTCTGATTTTGGATTGGATCAGCCTCTTAATGCCAGATATATGTCCGAT TTTTTGATTccTTTGCCAAAACATTTGACTGC?????????????????? GTCCTCAAGGTCGGAGTGTACCTGGAAAATGGTTGGGAGAGAGGTGAGAT GGATCACGATAGAACTGTTTTTCAATGGTTAGATCAACAACCTCCATCTT TGCAAATGCTATACGTAGAGTCATGGTTGATGAAGAGGGCGAGTATATTA CTGTTTTGTATGTTAGTTTTGGATCTACTTCTGAAGTTGATGAAAAAGAT GACAAAACGCTAGAGTGCTAAAGCAGAAGGCCGATGTTTCCCTTATGAAG TTTTTGGAAATTGCTAGAGGTTTGGTTGATTCCAAACAAAGTTTTTTATG GGGGGAAGTTCATATGAGAGTTTGGAATCCCTAGTGTCCTACATTTCTTC GGTTGTTAGACCAGGATTTGTCAAAGGATCTACTTGGGTCGAACCTTTGC GC????? CAGATGGATTTTTGGGAGAAAGAGGAAGAATTGTCAAATGGGTTCCACAG ( Sequence encoding SEQ ID NO : 7 codon optimized CAAGAAGTTTTGGCTCATGGTGCTATTGGTGCTTTTTGGACTCATTCTGG for expression in Escherichia coli ) SEQ ID NO : 8 ATGGAACTCTACTTTGGAATCTGTTTGTGAAGGTGTTCCAATGATTTTTT ATGGAAAATAAAACCGAAACCACCGTccGTCGCCGTCGTCGTATCATTCT CTGATTTTGGTTTGGATCAACCATTGAATGCTAGATACATGTCTGATGTT GTTcccGGTccCGTTCCAAGGTCACATCAAC?CGATTCTGCAGCTGGCCA TTGAAAGTTGGTGTTTATTTGGAAAATGGGTGGGAAAGAGGTGAAATTGC ACGTGCTGTATAGCAAAGGTTTCTCTATCACCATCTTCCATACGAACTTC CAATGCTATTAGAAGAGTCATGGTTGATGAAGAAGGAGAATACATTAGAC AACAAACCGAAAACCTCTAACTACCCGCACTTTACGTTCCGTTTTATTCT AAAATGCTAGAGTTTTGAAACAAAAAGCTGATGTTTCTTTGATGAAGGGT GGATAACGACCCGCAGGATGAACGCATCAGTAATCTGCCGACCCATGGTC GGATCTICTTATGAATCTTIGGAATCTTIGGTTT????????????c??? CGCTGGCGGGTATGCGTATTCCGATTATCAACGAACACGGCGCAGATGAA TTAA ??GCGTCGCGAACTGGAACTGCTGATGCTGGcc???GAAGAAGATGAAGA ( Sequence encoding SEQ ID NO : 5 codon optimized AGTTAGTTGCCTGATCACCGACGCACTGTGGTATTTTGCCCAGAGTGTTG for expression in Pichia pastoris ) SEQ ID NO : 6 CAGATTcccTGAACCTGCGTCGCCTGGTccTGATGACCAGC?????GTTC ATGCATCAACATCAACACCAATCTGGATCTATGGAGAACAAGACCGAGAC AATTTTCATGCCCACGTTTCCCTGCCGCAGTTCGATGAACTGGGTTATCT TACAGTTAGAAGAAGAAGAAGAATAATCCTGTTTCCAGTACCATTCCAAG GGACCCGGATGACAAAACCCGCCTGGAAGAACAAGCTTCAGGCTTTCCGA GACACATCAAC?CAATCTTGCAGTTAGCAAATGTACTTTATTCTAAAGGC TGCTGAAAGTCAAAGATATTAAAAGTGCGTACTCCAACTGGCAGATTCTG TTTAGTATTACGATTTTTCACACTAATTTTAATAAGCCAAAAACATCCAA AAAGAAATCCTGGGTAAAATGATCAAACAAACCCGTGCAAGTTCCGGCGT TTACCCTCACTICACATICAGATTTATCTTGGATAACGATccTCAAGATG CATCTGGAATTcc??CAAAGAACTGGAAGAATCAGAACTGGAAACGGTGA AACGTATCTCCAACCTGCCAACACATGGACCATTGGCCGGTATGCGTATT TTCGCGAAATCCCGGCTCCGTCTTTTCTGATTCCGCTGCCGAAACATCTG CCTATAATCAACGAGCATGGTGCTGATGAGCTTAGACGTGAACTGGAACT ACCGCGTCATCGAGC?????GCTGGATCACGACCGTACGGTGTTT CAGTG GTTGATGCTGGCATCGGAGGAAGATGAAGAGGTTAGTTGCTTGATAACGG GCTGGATCAGCAACCGCCGAGTTccGTGCTGTACGTTAGCTICGGTAGCA ATGCCCTCTGGTATTTCGCACAATCAGTCGCTGACTCCTTGAACCTTAGG CCTCTGAAGTGGATGAAAAAGACTTTCTGGAAATCGCTCGTGGCCTGGTT AGATTGGTATTGATGACTAGTTCGTTGTTCAACTICCATGCCCATGTT?? GATTCAAAACAATCGTTccTGTGGGTGGTTcccccGGGTTTTGTGAAAGG TTTGCCTCAATTTGATGAGCTGGGTTATTTGGATCCTGACGATAAGACTC CAGCACGTGGGTTGAACCGCTGCCGGATGGCTTCCTGGGTGAACGTGGTC GTTTAGAAGAACAGGCGTCAGGCTTCCCCATGTTAAAGGTTAAAGATATT GCATTGTCAAATGGGTGCCGCAGCAAGAAGTGCTGGCACATGGTGCTATC AAGTCCGCCTATTCTAACTGGCAAATTCTCAAAGAGATTCTAGGGAAAAT GGCGCGTTTTGGACCCACTCAGGTTGGAACTCGACGCTGGAAAGCGTTTG GATTAAACAAACCAAGGCCTCTICAGGAGTAATCTGGAACAGTTTCAAAG TGAAGGTGTcccGATGATTTTc?cGGATTTTGGCCTGGACCAGccGcTGA AACTAGAAGAATCCGAGTTGGAAACTGTTATTCGTGAAATCCCTGCTCCA ATGCACGTTATATGAGCGATGTTCTGAAAGTCGGTGTGTACCTGGAAAAC ?????ccTTATC?CATTACCAAAGCAcc?????????ccTCTAG?????? GGTTGGGAACGCGGCGAAATTGCGAATGCCATCCGTCGCGTTATGGTCGA ?cTGGACCATGATAGAACAGTCTTTCAGTGGCTcGATCAGCAACC????? TGAAGAAGGCGAATATATCCGTCAGAATGCTCGCGTCCTGAAACAAAAAG ?????GTCTTGTACGTTAGTTTTGGTTcCACCTcGGAAGTAGATGAAAAA CGGACGTTAGTCTGATGAAAGGCGGTTCATCGTACGAATCCCTGGAATCA GACTTTCTGGAAATTGCTcGAGGACTAGTTG???ccAAGCAATcc????? CTGGTCTCCTACATTTCTTCTCTGGGCTCGCATCATCATCATCATCATTA GTGGGTTGTTAGACCTGGATTCGTAAAAGGATCCACCTGGGTAGAACCCC TCCCAGATGGATTTTTGGGCGAAAGGGGAAGAATTGTTAAATGGGTGCCT [0166 ] In certain embodiments , the nucleic acid molecule CAACAAGAAGTTTTAGCTCATGGGGCCATTGGAGCTTTTTGGACTCATAG encodes an UGT76G1 glucosyltransferase and comprises TGGATGGAATTCTACCTTAGAATCTGTTTGTGAAGGAGTTCCAATGATTT the nucleotide sequence as set forth in Gen Bank Accession number AY345974 . 1 or a variant or fragment thereof. US 2018 /0264122 A1 Sep . 20 , 2018 32

[0167 ] In certain embodiments , the nucleic acid comprises a sequence encoding UGT76G2 glucosyltransferase . In spe GTATTGTGAAATGGGTTCCGCAGCAAGAAGTGCTAGCTCATGGAGCAATA- continued cific embodiments , the nucleic acid comprises a sequence encoding UGT76G2 glucosyltransferase having the amino GGCGCATTCTGGACTCATAGCGGATGGAACTCTACGTTGGAAAGCGTTTG acid sequence as set forth in SEQ ID NO : 27 and listed below TGAAGGTGTTCCTATGATTTTcTCGGCTTTTGCGTTCGATCAACCGTTGA or variants and fragments thereof. ATGCTAGATACATGAGTGATGTTTTGAAGGTAGGGGTGTATTTGGAAAAT

SEQ ID NO : 27 GGGTGGGAAAGAGGAGAGATAGCAAATGCAATAAGAAGAGTTATGGTGGA MENKTETTVRRRRRIILFPVPVOGHINPILOLANVLYSKGFSITIFHTNF TGAAGAAGGAGGATACATTAGACAGAATGCAAGTGTTTTGAAACAAAAGG NKPKTSNYPHFTFRFILDNDPODVRISNLPTHGPLTVMRILIINEHGADE CAGATGTTTCTTTGATGAAGGGTGGTTCGTCTTACGAATCATTAGAGTCT LORELELLMLASEEDGEVSCLITDOIWYFTOSVADSLNLRRLVLMTSSLF ???GTTGCTTACATTTCATCGTTGTAA NFHAHVSLPQFDELGYLDPDDKTRLEEQASGFPMLKVKDIKCGFSMWKOG [0169 ] In certain embodiments , the nucleic acid comprises a sequence encoding UGT76H1 glucosyltransferase . In spe KEIFENITKQTKASSGVIWNSFKELEESELETVIREIPAPSFLIPLPKHL cific embodiments , the nucleic acid comprises a sequence TASSSSLLDHDRTVFPWLDQQPSRSVLYVSFGSATEVDAKDFLEIARGLV encoding UGT76H1 glucosyltransferase having the amino acid sequence as set forth in SEQ ID NO : 29 and listed below DSKOSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWVPQQEVLAHGAI or variants and fragments thereof. GAFWTHSGWNSTLESVCEGVPMIFSAFAFDQPLNARYMSDVLKVGVYLEN GWERGEIANAIRRVMVDEEGGYIRONASVLKOKADVSLMKGGSSYESLES SEQ ID NO : 29 MLOLATYLHSOGISITIAQYPNFNSPDSSNHPELTFLPLSSGNLSVADIS LVAYISSL GGFFKFIQTLNHNCKPHFREYLVQNMSSDDKESIVIIRDNLMFFAGEIAG [0168 ] In specific embodiments , the nucleic acid com prises a sequence encoding UGT76G2 glucosyltransferase ELGLPSIILRGSNAVML TASDII POLHOEGRFPPPDSLLOETIPELVPFR and having the nucleic acid sequence as set forth in SEQ ID NO : 28 and listed below or variants and fragments thereof. YKDLPFIGYPIHQTLEFSITMMTPKS PASAILINTLEFLEQSALTQIRDH YKVPVFTIGPLHKIVTTRSTSILEEDTSCINWLDKOSPKSVVYVSLGSLA SEQ ID NO : 28 KLDEKVASEMACGLAMSNHKFLWVVRPGMVHGFEWVEFLPDSLVGEMKAR ATGGAAAATAAAACGGAGACCACCGTTCGCCGGCGCCGGAGAATAATATT GLIVKWAPQTTVLAHNAVGGFWSHCGWNSTIECLAEGVPMMCQPFFADQL ATTCCCGGTACCAGTTCAAGGCCACATTAACCCAATTCTTCAGCTAGCCA LNARYVSDVWKTGFEIVIEKGEIACAIKRVLVDEEGEEMRQRAMEIKEKV ATGTGTTGTACTCCAAAGGATICAGTATCACCATCTTTCACACCAACTIC KIAINDGGSSYDSFKDLVAFISSL AACAAAcccAAAACATCTAATTAcccTCACTICAc???cAGATTCATCCT [0170 ] In specific embodiments , the nucleic acid com CGACAACGAC?CACAAGACGTACGCATT?????????ccGACTCATGG?? prises a sequence encoding UGT76H1 glucosyltransferase and having the nucleic acid sequence as set forth in SEQ ID CGCTCACTGTTATGCGGATTcTGATTATCAACGAACACGGAGCTGACGAA NO : 30 and listed below or variants and fragments thereof. TTACAACGCGAACTGGAACTGTTGATGTTAGCTTCTGAAGAAGATGGAGA GGTATCGTGTTTAATCACCGATCAGATTTGGTACTTCACGCAATCTGTTG ATGCTICAGC??GCAACTTACCTCCATICTCAAGGGATTICAATAACCAT ??GACAGT????????ccGACGGCTTGTTTTGATGACAAGCAGCTTGTTT CGCTCAGTACCCCAACTTCAACTCGCCGGATTCTTCCAACCATCCAGAAC AATTTTCATGCACATGTTTC????ccTCAGTTTGATGAGCTTGGTTACCT ???????cc?????????cc?ccGGCAACTTATCCGTCGCCG??????cc CGATCCTGATGACAAAACCCGTTTGGAAGAACAAGCGAGTGGGTTTCCTA GGCGGCTTTTTCAAGTTCATccAAACTcTTAACCATAACTGCAAAccccA TGCTGAAAGTGAAAGATATCAAGTGTGGTTTTTCGATGTGGAAACAAGGC ???ccGGGAATACCTIGTICAGAACATGAGTTcTGATGATAAGGAATCAA AAAGAGATATTCGAGAACATTACGAAACAAACAAAAGCATCTTCAGGAGT ?cGTTATCATcCGTGATAATCTCATGTTTTTcGccGGAGAAATCGCCGGC CATCTGGAACTCATTTAAGGAACTCGAAGAGTCTGAGCTCGAAACTGTTA GAGCTGGGTCTGcc??cGATCATTTTACGTGGCAGCAATGCTGTCATGTT ?ccGTGAGATcccccc?ccAAGTTICTTG?T??????ccccAAGCATTTG GACTGCTAGCGAcATCATcccTCAACTICATCAAGAAGGTCGTTTTccGc ACAGcc????CCAGCAGCTTACTAGACCACGATCGAACCGTTTTTCCATG CACCAGATTCTTTGTTGCAGGAAACAATTCCAGAACTGGTTCCATTCAGA GTTAGACCAACAACCGTCACGTTCGGTACTGTATGTTAGTTTTGGTAGTG TACAAAGATCTACCATTTATTGGCTATCCAATACATCAAACCCTTGAATT CTACTGAAGTGGATGCGAAAGATTTCTTGGAAATAGCTCGTGGGTTGGTT TAGTATCACCATGATGAccccCAAATCAC??????cccccATT??????? GATAGCAAGCAGTCGTTTTTATGGGTGGTTCGACCTGGTTTTGTCAAGGG ACAcccTCGAATT???TGAACAATCGGCATTAAC?CAGATccGTGATCAT TTCGACGTGGGTCGAACCGTTGCCAGATGGGTTCTTGGGTGAAAGAGGAC TACAAAGTTCCAGTTTTTACAATCGGACCATTGCACAAAATAGTCACAAC US 2018 /0264122 A1 Sep . 20 , 2018 33

- continued - continued TCGTTCCACTAGCATTCTTGAAGAAGATACAAGTTGCATCAATTGGTTAG CGCTCCCGCGCGTCGAGGGGCTCCCCGACGGCGCCGAGTCCACCAACGAC ATAAACAATCACCCAAATCAGTGGTTTATGTGAGTTTAGGAAGCTTAGCA GTCCCCCACGACAGGCCGGACATGGTCGAGCTCCACCGGAGGGCCTTCGA AAGTTGGATGAAAAGGTTGCATCTGAAATGGCATGTGGTTTAGCCATGAG CGGGCTcccccccccc????cGGAGTTCTIGGGCAccGcGTGCGCCGACT TAACCATAAGTTCCTATGGGTGGTTCGACCCGGTATGGTTCATGGGTTTG AATGGGTCGAGTTTTTGccGGATAGTTTGGTGGGTGAAATGAAGGCTAGA GGGT CATCGTCGACGTC?????????TGGGCCGCAGCCGCCGC???CGAG CACAAGGTGCCATGTGCAATGATGTTGTTGGGc???GCACATATGATCGC GGTTTGATTGTGAAATGGGCACCCCAGACGACGGTTTTGGCGCATAACGC TTCCATAGCAGACAGACGGCTCGAGCGCGCGGAGACAGAGTCGCCTGCGG GGTTGGTGGATTTTGGAGTCATTGCGGTTGGAACTCGACCATAGAATGCT CTGCCGGGCAGGGACGCCCAGCGGCGGCGCCAACGTTCGAGGTGGCGAGG TAGCTGAAGGGGTCCCGATGATGTGTCAACCGTTTTTTGCTGATCAGTTG ATGAAGTTGATACGAACCAAAGGCTCATCGGGAATGTCCCTCGCCGAGCG TTGAATGCTAGGTATGTGAGTGATGTTTGGAAGACGGGTTTTGAGATTGT ?????ccTTGACCCTCTCGAGGAGCAGCCTCGTCGTCGGGCGGAGCTGCG TATCGAGAAAGGTGAGATTGCGTGCGCGATTAAACGAGTTTTGGTGGATG TGGAGTTCGAGCCGGAGACCGTCCCGCTCCTGTCGACGCTCCGCGGTAAG AAGAAGGCGAAGAAATGAGGCAGAGAGCTATGGAGATTAAAGAAAAGGTT CCTATTACCTTCCTTGGCCTTATGCCGCCGTTGCATGAAGGCCGCCGCGA AAAATTGCAATCAACGATGGTGGTTCTTCTTATGACTCGTTCAAGGACTT GGACGGCGAGGATGCCACCGTccGcTGGCTCGACGCGCAGccGGCCAAGT GGTGGCGTTTATTTCATCACTCTAA ccGTCGTGTACGTCGCGCTAGGCAGCGAGGTGCCACTGGGAGTGGAGAAG [0171 ] In certain embodiments , the nucleic acid comprises a sequence encoding Oryza sativa Os03g0702000 or GTCCACGAGCTCGCGCTCGGGCTGGAGCTCGCCGGGACGCGCTTCCTCTG Os03g0702000 - like glucosyltransferase . Os03g0702000 GGCTCTTAGGAAGCCCACTGGCGTCTCCGACGCCGACCTCCTCCCCGCCG like glucosyltransferase include for example , othermembers of the UGT91clade such as UGT91D1 or UGT91D2. In GCTTCGAGGAGCGCACGCGCGGCCGCGGCGTCGTGGCGACGAGATGGGTT certain embodiments , the nucleic acid comprises a sequence encoding Os03g0702000 glucosyltransferase having the ?cTCAGATGAGCATACTGGCGCACC?CGCCGTGGGCGCGTTccTGAC?CA amino acid sequence as set forth in SEQ ID NO : 9 and listed ??GCGGCTGGAACTcGACCATCGAGGGGCTCATGTTcGGCCAcccGc??? below or a variant or fragment thereof. TCATGCTGccGATC??cGGCGACCAGGGAccGAACGCGCGGCTAATCGAG

SEO ID NO : 9 GCGAAGAACGCCGGATTGCAGGTGGCAAGAAACGACGGCGATGGATCGTT MHQHQHQSGSMDSGYSSSYAAAAGMHVVICPWLAFGHLLPCLDLAQRLAS CGACCGAGAAGGCGTCGCGGCGGCGATTCGTGCAGTCGCGGTGGAGGAAG RGHRVSFVSTPRNISRLPPVRPALAPLVAFVALPLPRVEGLPDGAESTND AAAGCAGCAAAGTGTTTCAAGCCAAAGCCAAGAAGCTGCAGGAGATCGTC VPHDRPDMVELHRRAFDGLAAPFSEFLGTACADWVIVDVFHHWAAAAALE GCGGACATGGCCTGCCATGAGAGGTACATCGACGGATTCATTCAGCAATT HKVPCAMMLLGSAHMIASIADRRLERAETESPAAAGGGRPAAAPTFEVAR GAGATCTTACAAGGATTGA MKLIRTKGSSGMSLAERFSLTLSRSSLWVGRSCVEFEPETVPLLSTLRGK [0173 ] In certain embodiments , the nucleic acid molecule PITFLGLMPPLHEGRREDGEDATVRWLDAQPAKSVVYVALGSEVPLGVEK encodes Os03g0702000 glucosyltransferase and comprises the sequence as set forth in GenBank Accession number VHELALGLELAGTRFLWALRKPTGVSDADLLPAGFEERTRGRGVVATRWY XM _ 015773655 or a variant or fragment thereof. [0174 ] In certain embodiments , the nucleic acid comprises POMSILAHAAVGAFLTHCGWNSTIEGLMFGHPLIMLPIFGDQGPNARLIE a sequence encoding UGT91D1 glucosyltransferase . In cer AKNAGLQVARNDGDGSFDREGVAAAIRAVAVEEESSKVFQAKAKKLQEIV tain embodiments , the nucleic acid comprises a sequence encoding UGT91D1 glucosyltransferase having the amino ADMACHERYIDGFIQQLRSYKD acid sequence as set forth in SEQ ID NO :31 and listed below [ 0172 ] In certain embodiments , the nucleic acid molecule or a variant or fragment thereof . encodes Os03g0702000 glucosyltransferase and comprises a nucleotide sequence as set forth in SEQ ID NO : 10 and as SEQ ID NO : 31 detailed below or a variant or fragment thereof. MYNVTYHQNSKAMATSDSIVDDRKQLHVATFPWLAFGHILPFLQLSKLIA EKGHKVSFLSTTRNIQRLSSHISPLINVVOLTLPRVQELPEDAEATTDVH SEQ ID NO : 10 ATGCATCAGCACCAACATCAGAGCGGTTCTATGGACTCCGGCTACTCCTC PEDIQYLKKAVDGLQPEVTRFLEQHSPDWIIYDFTHYWLPSIAASLGISR CTCCTACGCCGCCGCCGCCGGGATGCACGTCGTGATCTGCCCGTGGCTCG AYFCVITPWTIAYLAPSSDAMINDSDGRTTVEDLTTPPKWFPFPTKVCWR cCTICGGCCACCTGCTccCGTGCCTCGAC??cGcccAGCGCCTCGCGTCG KHDLARMEPYEAPGISDGYRMGMVFKGSDCLLFKCYHEFGTQWLPLLETL CGGGGCCACCGCGTGT??????????CAccccccGG?????????????? HQVPVVPVGLLPPEIPGDEKDETWVSIKKWLDGKOKGSVVYVALGSEALV CCCGCCGGTGCGCCCCGCGCTCGCGCCGCTCGTCGCCTTCGTGGCGCTGC SQTEWELALGLELSGLPFVWAYRKPKGPAKSDSVELPDGFVERTRDRGL US 2018 /0264122 A1 Sep . 20 , 2018 34

- continued encoding UGT91D2 glucosyltransferase having the amino acid sequence as set forth in SEQ ID NO : 33 and listed VWTSWAPOLRILSHESVCGFLTHCGSGSIVEGLMFGHPLIMLPIFCDQPL below or a variant or fragment thereof. NARLLEDKOVGIEIPRNEEDGCLTKESVARSLRSVVVENEGEIYKANARA LSKIYNDTKVEKEYVSOFVDYLEKNARAVAIDHES SEQ ID NO : 33 MATSDSIVDDRKQLHVATFPWLAFGHILPYLQLSKLIAEKGHKVSFLSTT 101751 In certain embodiments , the nucleic acid molecule encodes UGT91D1 glucosyltransferase and comprises a RNIQRLSSHISPLINVVOLTLPRVOELPEDAEATTDVHPEDIPYLKKASD nucleotide sequence as set forth in SEQ ID NO : 32 and as GLOPEVTRFLEQHSPDWIIYDYTHYWLPSIAASLGISRAHFSVTTPWAIA detailed below or a variant or fragment thereof. YMGPSADAMINGSDGRTTVEDLTTPPKWFPFPTKVCWRKHDLARLVPYKA PGISDGYRMGLVLKGSDCLLSKCYHEFGTQWLPLLETLHQVPVVPVGLLP SEQ ID NO : 32 ATGTACAACGTTACTTATCATCAAAATTCAAAAGCAATGGCTACCAGTGA PEIPGDEKDETWVSIKKWLDGKOKGSVVYVALGSEVLVSQTEVVELALGL CTCCATAGTTGACGACCGTAAGCAGCTTCATGTTGCGACGTTCCCATGGC ELSGLPFVWAYRKPKGPAKSDSVELPDGFVERTRDRGLVWTSWAPOLRIL TTGCTTTCGGTCACATCCTCCCTTTCCTTCAGCTTTCGAAATTGATAGCT SHESVCGFLTHCGSGSIVEGLMFGHPLIMLPIFGDOPLNARLLEDKOVGI GAAAAGGGTCACAAAGTCTCGTTTCTTTCTACCACCAGAAACATTCAACG EIPRNEEDGCLTKESVARSLRSVVVEKEGEIYKANARELSKIYNDTKVEK ?????????????????cGCCACTCATAAATGTTGTICAACTCACACT?? EYVSQFVDYLEKNARAVAIDHES CACGTGTCCAAGAGCTGCCGGAGGATGCAGAGGCGACCACTGACGTCCAC 10177 ] In certain embodiments , the nucleic acid molecule encodes UGT91D2 glucosyltransferase and comprises a CCTGAAGATATTCAATATCTCAAGAAGGCTGTTGATGGTCTTCAACCGGA nucleotide sequence as set forth in SEQ ID NO : 34 and as GGTCAcccGGTTICTAGAACAACACTc?ccGGACTGGATTATTTATGATT detailed below or a variant or fragment thereof . TTACTCACTACTGGTTGCCATCCATCGCGGCTAGCCTCGGTATCTCACGA SEQ ID NO : 34 Gcc????cTGCGTCATCACTcCATGGACCATTccTTATTIGGCAccc?? ATGGCCACATCTGACTCTATCGTTGATGACAGAAAACAATTGCATGTTGC ATCTGACGCCATGATAAATGATTCAGATGGTCGAACCACGGTTGAGGATC ??????ccCATGGTTGGccTTTGG???????c?acccTACTTGCAATTGT TCACGACACCGCCCAAGTGGTTTccc???ccGACCAAAGTATGCTGGCGG CAAAGCTGATTGCAGAAAAAGGTCATAAGGTGTCCTTTTTGTCTACCACA AAGCATGATCTTGCCCGAATGGAGCCTTACGAAGCTCCGGGGATATCTGA AGAAACATCCAGAGACTAAGTTCTCATATTTCTCCATTGATTAATGTGGT TGGATACCGTATGGGGATGGTTTTTAAGGGATCTGATTGTTTGCTTTTCA TCAGTTGACCTTGCCTAGAGTCCAAGAAC??cccGAAGACGCAGAAGCTA AATGTTACCATGAGTTTGGAACTCAATGGCTACC??????GGAGACACTA CTACTGATGTTCAcccTGAAGATATC?CATATCTAAAGAAGGCATCTGAT CACCAAGTACCGGTGGTTCCGGTGGGATTACTGCCGCCGGAAATACCCGG GGACTTCAACCAGAAGTAACCAGGTTTTTGGAGCAGCACAGTCCTGACTG AGACGAGAAAGATGAAACATGGGTGTCAATCAAGAAATGGCTCGATGGTA GATTATCTATGATTATACTCATTACTGGCTTCCATCCATCGCAGCTAGTC AACAAAAAGGCAGTGTGGTGTACGTTGCATTAGGAAGCGAGGCTTTGGTG TAGGCATTTCCAGAGCTCATTTCTCTGTCACTACCCCATGGGCAATTGCA AGCCAAACCGAGGTTGTTGAGTTAGCATTGGGTCTCGAGCTTTCTGGGTT TATATGGGTCCTTCTGCTGATGCAATGATCAACGGTTCTGATGGTAGGAC GCCATTTGTTTGGGCTTATAGAAAACCAAAAGGTCCCGCGAAGTCAGACT CACTGTTGAAGATTTAACTACACCTCCAAAGTGGTTCCCATTTCCTACTA CGGTGGAGTTGCCAGACGGGTTCGTGGAACGAACTCGTGACCGTGGGTTG AAGTTTGTTGGCGAAAACACGATCTGGCACGTTTGGTCCCATATAAGGCT GTCTGGACGAGTTGGGCACCTCAGTTACGAATACTGAGCCACGAGTCAGT CCAGGTATCTCCGATGGATATCGAATGGGTCTGGTGCTAAAGGGTTCTGA TTGTGGTTTCTTGACTCATTGTGGT???GGATCAATTGTGGAAGGGC??? TTGTCTGTTATCTAAGTGTTACCACGAATTTGGAACTCAATGGCTTCCTC TGTTTGGTCACCCTCTAATCATGCTACCGATTTTTTGTGACCAACCTCTG ??TT?G?G???cTGCATCAAGTTcCAGTTGTTccTGTCGGTCTGCTACCA AATGCTCGATTACTGGAGGACAAACAGGTGGGAATCGAGATACCAAGAAA CCTGAAATTCCCGGTGACGAAAAGGACGAAACTTGGGTTTCCATAAAAAA TGAGGAAGATGGTTGCTTGACCAAGGAGTCGGTTGCTAGATCACTGAGGT ATGGCTGGATGGTAAGCAGAAGGGTAGTGTTGTATATGTCGCTTTAGGCT CCGTTGTTGTGGAAAACGAAGGGGAGATCTACAAGGCGAACGCGAGGGCG CCGAGGTTTTGGTATCCCAGACTGAAGTTGTGGAACTTGCCTTAGGATTG CTGAGTAAAATCTATAACGACACTAAGGTGGAAAAAGAATATGTAAGCCA GAGTTGTccGGTTTGCCATTcG???GGGCATATAGAAAGCCAAAGGGACC ATTCGTAGACTATTTGGAAAAGAATGCGCGTGCGGTTGCCATCGATCATG AGCTAAGTCAGACTCAGTTGAATTGCCAGATGGTTTCGTAGAAAGGACAA AGAGTTAA GAGACAGAGGATTGGTTTGGACATCATGGGCCCCACAATTGAGAATTCTG [0176 ] In certain embodiments , the nucleic acid comprises AGTCATGAAAGTGTGTGTGGATTCTTGACTCACTGTGGCTCTGGCAGTAT a sequence encoding UGT91D2 glucosyltransferase . In cer tain embodiments , the nucleic acid comprises a sequence US 2018 /0264122 A1 Sep . 20 , 2018 35

- continued - continued TGTTGAAGGA?TGATGTTTGGACACCCACTGATAATGTTGCCAATCTTCG AATATTGATCAAGCACGTTGGGTCTTCACAAATAGTTTTTACAAGCTCGA GTGACCAACCTCTGAATGCAAGATTGCTGGAGGATAAACAAGTTGGTATC GGAAGAGGTAATAGAGTGGACGAGAAAGATATGGAACTTGAAGGTAATCG GAAATCCCAAGAAACGAGGAAGACGGCTGCCTGACTAAGGAATCAGTTGC GGCCAACACTTCCATCCATGTACCTTGACAAACGACTTGATGATGATAAA ACGTAGTTTAAGATCTGTAGTTGTTGAAAAAGAAGGTGAAATATATAAGG GATAACGGATTTAATCTCTACAAAGCAAACCATCATGAGTGCATGAACTG C?AACGCTAGAGAACTTTCAAAGATATACAATGATACCAAGGTGGAGAAA GTTAGACGATAAGCCAAAGGAATCAGTTGTTTACGTAGCATTTGGTAGCC GAATATGTTTCACAGTTTGTGGACTATTTGGAGAAAAACGCTAGAGCCGT TGGTGAAACATGGACCCGAACAAGTGGAAGAAATCACACGGGCTTTAATA TGCTATCGATCACGAATCATAG GATAGTGATGTCAACTICTTGTGGGTTATCAAACATAAAGAAGAGGGAAA [ 0178 ] In certain embodiments , the nucleic acid comprises a sequence encoding Stevia rebaudiana UDP - glycosyltrans GCTCCCAGAAAATCTTTCGGAAGTAATAAAAACCGGAAAGGGTTTGATTG ferase 74G1. In certain embodiments , the nucleic acid TAGCATGGTGCAAACAATTGGATGTGTT?????????????GTAGGATGC comprises a sequence encoding Stevia rebaudiana UDP glycosyltransferase 74G1 which comprises the amino acid ??TGTTACACATTGTGGGTTCAACTCAAC???TGAAGCAATAAGTCTIGG sequence as set forth in SEQ ID NO : 13 and as listed below AGTccccGTTGTTGCAATGCC????????CGGATCAAACTACAAATGCCA or a variant or fragment thereof. AGCTTCTAGATGAAATTTTGGGTGTTGGAGTTAGAGTTAAGGCTGATGAG

SEO ID NO : 13 AATGGGATAGTGAGAAGAGGAAATCTTGCGTCATGTATTAAGATGATTAT MAEQQKIKKSPHVLLIPFPLQGHINPFIQFGKRLISKGVKTTLVTTIHTL GGAGGAGGAAAGAGGAGTAATAATCCGAAAGAATGCGGTAAAATGGAAGG NSTLNHSNTTTTSIEIQAISDGCDEGGFMSAGESYLETFKOVGSKSLADL ATTTGGCTAAAGTAGCCGTTCATGAAGGTGGTAGCTCAGACAATGATATT IKKLOSEGTTIDAIIYDSMTEWVLDVAIEFGIDGGSFFTQACVVNSLYYH GTCGAATTTGTAAGTGAGCTAATTAAGGCTTAA VHKGLISLPLGETVSVPGFPVLQRWETPLILQNHEQIQSPWSQMLFGQFA [0180 ] In certain embodiments , the nucleic acid molecule NIDQARWVFTNSFYKLEEEVIEWTRKIWNLKVIGPTLPSMYLDKRLDDDK encodes Stevia rebaudiana UDP - glycosyltransferase 74G1 and comprises the sequence as set forth in Gen Bank DNGFNLYKANHHECMNWLDDKPKESWVYVAFGSLVKHGPEQVEEITRALI Accession number AY345982 or a variant or fragment DSDVNFLWVI KHKEEGKLPENLSEVIKTGKGLIVAWCKOLDVLAHESVGC thereof. [0181 ] In other embodiments , the invention provides for FVTHCGFNSTLEAISLGVPWAMPQFSDOTTNAKLLDEILGVGVRVKADE nucleic acids comprising nucleotide sequences encoding a NGIVRRGNLASCIKMIMEEERGVIIRKNAVKWKDLAKVAVHEGGSSDNDI cyclodextrin glucanotransferase (WO1996033267 ; U . S . Pat . No . 6 ,271 ,010 ) . VEFVSELIKA [0182 ] Also provided are nucleic acids comprising nucleo [0179 ] In certain embodiments , the nucleic acid molecule tide sequences that encode a sucrose synthase . Accordingly , encodes Stevia rebaudiana UDP - glycosyltransferase 7401 in certain embodiments , the nucleic acid comprises a and comprises a nucleotide sequence as set forth in SEQ ID sequence encoding sucrose synthase which comprises the amino acid sequence as set forth in SEQ ID NO : 15 , 17 , 19 , NO : 14 and as listed below or a variant or fragment thereof. 21, 23 or 25 and listed below or a variant or fragment thereof. SEO ID NO : 14 ATGGCGGAACAACAAAAGATCAAGAAATCACCACACGTTCTACTCATccc ( Stevia rebaudiana susi isoform ) ???cccTTTACAAGGCCATATAAAcccTTTCATccAGTTIGGCAAACGAT SEO ID NO : 15 MAERVLTRVHSLRERLDSTLATHRNEILLFLSRIESHGKGILKPHQVMTE ??????cCAAAGGTGTCAAAACAACACTTGTTACCACCAT?????????? FEAICKEDOS KLSDGAFYEVLKCTQEAIVQPPWVALAIRLRPGVWEYVRV AACTCAACCCTAAACCACAGTAACACCACCACCACCTCCATCGAAATCCA NVNVLVVEELSVPEYLHFKEELVNGTSNGNFVLELDFEPFTASFPRPTLT AGCAATTTCCGATGGTTGTGATGAAGGCGGTTTTATGAGTGCAGGAGAAT KSIGNGVEFLNRHLSAKMFHDKDSMHPLLDFLRTHHYKGKTMMLNDRION CATATTTGGAAACATTCAAACAAGTTGGGTCTAAATCACTAGCTGACTTA LNALQSVLRKASEYLSTLDAATPYSEFEHKFQEIGLERGWGDKAEVVMEM ATCAAGAAGCTTCAAAGTGAAGGAACCACAATTGATGCAATCATTTATGA IHMLLDLLEAPDACTLEKFLGRIPMVFNVILSPHGYFAQENVLGYPDTG TTCTATGACTGAATGGGTTTTAGATGTTGCAATTGAGTTTGGAATCGATG GQVVYILDQVPALEREMLKRIKEQGLDIIPRILIVTRLLPDAVGTTCGQR GTGGTTCGTTTTTCACTCAAGCTTGTGTTGTAAACAGCTTATATTATCAT LEKVFGAEHSHILRVPFRTEKGILRKWISRFEVWPYIETFTEDVAKEVTA GTTCATAAGGGTTTGATTTCTTTGCCATTGGGTGAAACTGTTTCGGTTCC ELQAKPDLIIGNYSEGNLVASLLAHKLGVTQCTIAHALEKTKYPDSDIYW TGGATTTCCAGTGCTTCAACGGTGGGAGACACCGTTAATTTTGCAGAATC KNFEEKYHFSSQFTADLIAMNHTDFIITSTFQEIAGSKDTVGQYESHTAF ATGAGCAAATACAGAGCCCTTGGTCTCAGATGTTGTTTGGTCAGTTTGCT US 2018 /0264122 A1 Sep . 20 , 2018 36

- continued - continued TMPGLYRVVHGIDVFDPKFNIVSPGADMGIYYSYTEKEKRLTALHPEIDE NRARNGEFYRYIADGRGVFVQPAFYEAFGLTVVEAMTCGLPTFATCHGGP LLFSSVENEEHLCVLKDKSKPILFTMARLDNVKNLTGLVEWYAKNDRLRE AEII EDGVSGFHIDPYHPDKMSTTLADFFQKCKEEPSYWGKISDGGLKRI LVNLVVVGGDRRKESKDLEEQAQMQKMHELIETYKLNGQFRWISSQMNRV SERYTWKIYSERLMTLAGVYSFWKYV SKLERRETRRYLEMFYILKFROLV

RNGELYRVIADTRGAFIQPAFYEAFGLTVVEAMTCGLPTFATLHGGPAEI KSVPLAVDEEP

IVHGKSGFHIDPYHGDQVTELLVNFFEKTKQDPGHWEAISKGGLQRIQEK ( Stevia rebaudiana SUS4 isoform ) SEQ ID NO : 21 YTWQIYSDRLLTLAGVYGFWKHVSKLDRLEIRRYLEMFYALKYRKLAESV MASASSSIMKRSESIVDTMPEALKQSRYHMKKCFLKYVEKGIRMMKRHHL PLAVDE IQEMETAIEDKDEKAQLLDGLLGYILCTTQEAAVVPPCVAFAIRPNPGFW ( Stevia rebaudiana SUS2 isoform ) SEQ ID NO : 17 EFVKVNSNDLSVDGITATDYLKF KEMIVDE TWAKDENALEIDFGSMDFNL MATSKLSRTHSMRERVEETLSAHRNEIVSLLSRYVAQGKAILQPHQILHE PNMSLSCSIGNGVNFTSKFITCKLYAQSSCOQLLVDYLLSLNHQGENLMI LENIIGDVTSROKLTDGPFGDALKTAQECIVLPPFVALAVRPRPGVWEYV NDALNSVSKLRAALIVAHASLSSLPNDTPYOSFELRFKEWGFEKGWGDNA RVDAYQLSVEQLTVSEYLTFKEELVGESNSSLMLELDFEPFNASFPRPTR SSSIGNGVQFLNRHLSSSMFRSKDCLEPLLDFLRTHRHNGHVMMLNDRIT ERARETIRFLLEVLQAPDPINLEALFSRIPNIFNVLFSIHGYFGQSNVL SMTRLOSSLVKAEEYLSKLPSDTDYSEFOYELOGMGFERGWGNNAERIIE GLPDTGGQVVYVLDQVVAMEEELLMRIKQQGLNFKPQILVVTRLLPDAKG MMHLLSDILQAPDPSILESFLARIPMVFNVVILSIHGYFGQANVLGLPDT TKCNQVLEPVLNTKHSHILRVPPRTDKGVLRKWVSRFDIYPYLENFTODA GGQIVYILDQVRALENEMLLKLKHQGLDIKPRILIVTRLIPDAKGTSCNQ SAKIIEMMEGKPDLIIGNYTDGNLVASLMANKLGTTLGTIAHALEKTKYE RLERVSGTEHTHILRVPFRTEKGILRKWISRFDVWPFLEKFTQDAASEIS DSDMNWKQFDPKYHFSCQFTADMIAMNSADFIITSTFQEIAGSKDRPGQY AELHGTPDLIIGNYSDGNLVASLLSYKMGVTQCNIAHALEKTKYPDSDLY ESHEAFTLPGLYRVVSGINVFDPKFNIASPGADOTVYFPYTETKKRFTAF WKKFDEKYHFSCQFTADLLAMNNADFIITSTYQEIAGTKNTVGQYESHSS QPAIEELLFSKVENEEHIGYLEDKTKPIIFSMARLDTVKNITGLTEWFGE FTLPGLYRVVHGIDVFDPKFNIVSPGADMSIYFSYTEKEKRLTSLHTTIE NKRLRSLVNLVIVAGFFDPSKSKDREEMAEIKKMHLLIEKYQLKGQIRWI KLLFDPTQTEDYIGNLSDKSKPIIFSMARLDHVKNITGLVEWYAKNEKLR AAQTDKNRNSELYRFIADSKGAFVQPALYEAFGLTVIEAMNCGLPTFATN GLANLVVVAGYNNVKRSSDREEIAEIEKMHQLIKKYKLDGOMRWISAQTN RAQNGELYRYIADGRGIFVQPAIYEAFGLTVVEAMTCGLPTFATCHGGPG QGGPAEIIVDGVSGFQIDPNFGDQSSNKIADFFQKCKEDPGYWNNISEGG EIIENGVSGFHIDPYHPDTASATMADFFOKCKEDPSYWFKISEAGLKRIY LKRIYECYTWKIYANKVLNMGNIYSFWKRLNKEQKEAKORYIELFYNLHY ERYTWKIYSERLMTLAGVYSFWKYVSKLERRETRRYLEMFYILKFRDLVK KNLVRTVPIASDEAQPAPVSRAKLATQPTRRTOSRLQRLFGA SVPVATDDEA ( Stevia rebaudiana SUS5 isoform ) SEQ ID NO : 23 ( Stevia rebaudiana SUS3 isoform ) MAASSSPIMKRSESVLDTMPEALRQSRYHMKKCFLKYVGKGKRMVKLHHL SEQ ID NO : 19 MATPKLTRTPSMRERLEETLSAHRNDIVSLLSRYVDQGKAILQPHHLLDE MQEMETVIEDKDEKAQLLEGLLGYILCTTQEAAVVPPYVAFAIRPNPGFW IDNFIGDQNCROKLADSLFGEILKSAQEGIILPPYVTLAVRPRPGVWDFL EFVKVNSNDLSVKGITSTDYLKFKEMIVDETWANDENALEIDFGAMDFNL RVNVDELSVEQLTVSEYLSFKEELVDGQSRNPFVLELDLEPFNATFPRMS PTMSLSSSIGNGVNFTSKFIISKLYAHSGSQLQSLVDYLLSLNHQGEKLM RSSSIGNGVQFLNRHLSSIMFRNKD CMDPFLDFLRAHKHKGYAMMLNDRI INDKLNTVSKLQAALIVAHSFLSSLPNDTPYQSFELRFKEWGFEKGWGDY QTMSRLESSLAKAEDHLSKLPPETPYSEFEYVLOGMGFERGWGDNCERVL GMMHLLSDILQAPDPSILEKFLGKMPMIFNVVVLSIHGYFGQANVLGLPD AERVQETIRFLLEVLQAPDPVNLEAFFSRVPNIFNIVLFSIHGYFGQSNV TGGOWYILDQVRSLENEMLLKLRHQGLDIKPKILIVTRLIPNAKGTSCN LGLPDTGGQVVYVLDQVVAMEEELLLRIKQQGLSFKPHILVVTRLLPDAK QRLEKVSGTEYTYILRVPFRTEKGILGKWLSRFDIWPYLEAFTTDAASEI GTECSQVLEPVLNTKHSHILRVPFRTEKGVLRKWVSRFDIYPYLEKFTQD AAELHGVPDLLIGNYSDGNLVASLLSNKLGVTOCNIAHALEKTKYPDSDL ASAKITEMMEGKPDLIIGNYTDGNLVASLMANKLGSTLGTIAHALEKTKY YWKKFEDKYHFSCQFTADLLAMNNADFIITSTYQEIAGTKNTVGQYENHS EDSDMKWKHLDTKYHFSCQFTADMIAMNSADFIITSTFQEIASKDRPGQ SFTLPGLYRVVHGIDVFDPKFNIVSPGADMAIYFSYADKERRLTSLHPTI YESHEAFTLPGLYRVVSGINVFDPKFNIASPGADQTVYFPYTETPKRFTT EKLLFDTEQNDVHIGNINDPSKPMIFTMARLDHVKNITGFVECYAKNNKL FQPAIQELLFSKVENDEHIGYLEDKNKPIIFSMARLDMVKNITGLTEWFG REHANLVVIAGYNDAKKSSDREEIAEI EKMHNLIKQYKLDGQMRWISAQT ENKRLRSLVNLVIVAGFFDPSKSKDREEMEEIKKMHLLIEKYELKGQIRW US 2018 /0264122 A1 Sep . 20 , 2018 37

- continued - continued IVAQTDKNRNSELYRCIADSKGAFVQPALYEAFGLTVIEAMNCGLPTFAT CTCACCACTATAAGGGAAAGACAATGATGTTGAATGATAGAATCCAAAAC NQGGPAEI IVDGVSGFQIDPNYGDESSNKIADFFQKCKQDPGYWNRISDG ??CAATGCTCTACAATCGGTGTTGCGAAAGGCGTCAGAGT?????????? GLMRIYECYTWKIYANKVLNMGNIYTFWKOLNKEOKDAKORYIELFYNOH ACTCGACGCAGCAACACCGTACTCTGAGTTTG??????????? CAAGAAA YKNLVRTVPIVSDEDDOVTRAKPATOPSTRRTOSALQRLLGA TCGGGTTGGAGAGAGGTTGGGGTGATAAAGCGGAGGTCGTAATGGAGATG ( Stevia rebaudiana SUS6 isoform ) SEO ID NO : 25 ATCCACATGCTICTAGACCTICTAGAAGCAC?CGACGCATGCACACTCGA MDFGIAETLAEALKONRYHARRCFERFTSRGKRMVKPQELLHMIEKTIDD GAAGTTTc?cGGAAGAATC?CAATGGTTTTCAATGTTGTCATTc???cGc KLERTKVLEGSMGQILSSTQEAIVIPPYVILGLRANPGQWAYVKINADDV CTCACGGC?????cGccCAAGAAAATGTGTTGGGATATC?CGACACTGGC TVESLTPSQYLKFKESIYDQEWAKDENALELDFGAFDFDTPRLILPSSIG NGLGYISKFMTSRIGGDLENAKPLLDHLLALKYHGEKLMINETIDTVSKL GGTCAGGTTGTTTACATCTTGGATCAAGTTccccc???GGAACGCGAGAT GCTCAAAAGGATTAAGGAGCAAGG???cG????????cc?cGTATATTGA OKALIVADVYLSAHPKDEQYQTLEPKLKEWGFEKGWGDTAERVRETMKML SEILQAPDPINMOSFFSRLPVVFNIVIFSIHGYFGQSDVLGLPDTGGQVV TTGTTACGAGGC??c??cccGACGCGGTIGGGACCACATGCGGGCAACGT TTAGAGAAAGTGTTTGGAGCCGAACACTCGCATATTCTTCGGGTCCCGTT YILDOVKALEEEILLRIKMOGLNAKPRILVVSRLIPDAOGTKCNEEMEPI LNTMHSHILRVPFRTSKGVVPQWVSRFDIYPYLERFSQDAASKILEVMEC TAGAAccGAAAAGGGTATT???cGTAAATGGATc???CGTTTTGAGGTGT KPDLILGNYTDGNIVASLIAKKFGVTOGTIAHALEKTKYEDSDVNWKNFE GGCCTTACATCGAGACTTTCACCGAGGATGTTGCTAAAGAAGTTACAGCA KKYHFSCOFTADLISMNAADFIITSTYOEIVGSKORPGOYETHGAFSMPG GAGTTGCAAGCAAAACCAGATTTGATCATTGGAAACTATAGTGAAGGAAA LCRVVSGINVFDPKFNIASPGAEQSVYFPYTEKEKRLTDFHPAIKELLFN TTTGGTTGCATCTTTGCTAGCTCACAAGTTGGGTGTCACTCAGTGTACCA EQDNDEHMGYLADVTKPIIFSMARLDTVKNITGLTEWFGKNKRLRSLVNL TTGCTCATGCTTTGGAGAAAACTAAATACCCGGATTCTGATATCTACTGG VVVAGFFDPSKSKDREEMEEI KKMHELIEKYKLKGQMRWIAAQNDRTRNG AAGAACTTTGAGGAGAAATATCATTTc????cGCAGTTTACCGCTGATCT ELYRCISDTKGAFVQPALYEAFGLTVIEAMNCGLPTFATNOGGPAEIIVD TATCGCTATGAACCATACCGACTTCATCATCACCAGTACTTTCCAAGAAA GVSGFHIDPVNGDESSNKIADFFTKCKVDGEYWDRVSQAGLORIYECYTW TTGCTGGAAGTAAGGACACGGTTGGACAGTACGAGAGTCATACCGCGTTC KMYANKALNMGSMYGFWRQLNKETKQAKORYIDILYNLQFKNLAKTIEIP ACAATGCCGGGATTGTATCGGGTGGTTCACGGGATCGATGTTTTTGACCC DFVTPKLOEPVKTEPTKPLOEARPREPVOKLVPEETRLPKLELTKLGOPN CAAATTCAATATTGTTTCACCCGGGGCCGATATGGGAATTTACTACTCGT LMSNARKPLIVLVSVLIVAYASKNLYRRYFK A?AccGAGAAAGAAAAGAGGCTCACTGCGCTICAcccTGAAATCGATGAA [ 0183] In certain embodiments, the nucleic acid molecule ???????TTAGTTccGTCGAAAACGAAGAACACTTATGTGTGTTGAAGGA encodes sucrose synthase and comprises a nucleotide sequence as set forth in SEQ ID NO : 16 , 18 , 20 , 22, 24 or 26 TAAGAGTAAACCAATCTTGTTCACAATGGCGCGATTGGATAATGTGAAGA and listed below or a fragment or variant thereof. ATTTAACCGGACTGGTTGAATGGTACGCTAAAAACGAccGcc??cGTGAG

( encodes SUS1 isoform ) ??cGTGAACCTCGTGGTCGTCGGTGGTGACCGAAGGAAAGAGTCGAAAGA SEO ID NO : 16 ATGGCGGAACGTGTACTCACTCGTGTTCACAGTCTTCGTGAGCGTCTCGA ???TGAAGAACAAGCTCAGATGCAGAAGATGCATGAACTTATCGAAACCT TTCAACTCTCGCAACTCATCGTAATGAAATCCTCTTGTTTCTTTCAAGGA ACAAACTCAACGGTCAGTICAGGTGG????ccTCACAAATGAACCGCGTG TTGAAAGCCATGGAAAAGGAATATTGAAGCCTCATCAAGTTATGACTGAA AGGAACGGTGAGTTGTATCGCGTTATTGCTGACACACGAGGTGCGTTTAT TTTGAAGCTATCTGCAAAGAAGATCAGAGCAAAC?????GATGGTGc??? CCAGCCTGCGTTTTACGAGGCGTTTGGGTTGACGGTTGTGGAGGCCATGA TTATGAAGTTCTTAAATGCACACAGGAAGCAATAGTGCAACCTCCATGGG CTTGTGGCCTGCCGACATTCGCGACACTTCATGGTGGGCCCGCTGAGATT TTGCACTCGCGATCCGTCTTCGACCCGGTGTTTGGGAATATGTTAGAGTC ATTGTTCACGGGAAATCCGGGTTCCATATTGACCCGTATCACGGTGACCA AATGTTAATGTTTTGGTGGTTGAAGAATTAAGTGTTCCTGAATATCTTCA CTTCAAAGAAGAATTGGTTAATGGAACATCGAATGGCAACTTCGTGTTGG GGTCACCGAGTTGCTGGTCAATTTCTTTGAGAAAACTAAACAAGACCCGG AACTGGATTTTGAACCTTTTACCGCATCGTTTCCTCGACCAACTTTAACC GTCATTGGGAGGCCATTTCCAAGGGTGGTCTGCAACGTATTCAGGAGAAA AAGTCTATTGGTAATGGTGTTGAGTTTCTAAACAGACATTTATCTGCTAA TACACGTGGCAGATTTATTCAGATAGGTTGTTGACGCTTGCCGGAGTTTA AATGTTTCATGATAAGGATAGCATGCAccc?????TTGATTTccTACGGA TGGATTCTGGAAGCATGTGTCGAAGCTTGACAGGCTCGAGATCCGTCGTT US 2018 /0264122 A1 Sep . 20 , 2018 38

- continued - continued ???TTGAAATGTTTTACGcGc????GTATCGCAAACTGGCTGAATCTGTT GGACTAGCAAACCTTGTTGTGGTTGCTGGTTATAATAATGTGAAGAGGTC CCATTGGCTGTTGATGAGTGA TAGTGACAGAGAAGAAATTGCAGAAATTGAAAAAATGCATCAACTTATTA ( encodes Sus2 isoform ) AGAAATACAAATTAGATGGTCAGATGAGATGGATTTCAGCACAAACAAAC SEQ ID NO : 18 ATGGCGACAAGTAAGTTGAGCAGAACGCATAGTATGCGTGAGCGTGTTGA CGCGCACAAAATGGTGAACTTTATCGCTATATTGCTGATGGAAGGGGAAT AGAAACTCTTTCCGCTCATCGCAACGAAATCGTTTCTCTTCTTTCTAGGT CTTTGTACAGCCCGCTATTTATGAAGCTTTTGGGCTGACAGTGGTGGAGG ATGTGGCTCAGGGGAAGGCGATATTGCAGCCGCATCAGATACTCCATGAA CCATGACTTGTGGGCTTCCAACATTTGCAACTTGCCATGGTGGGCCAGGA CTTGAGAATATCATCGGTGATGTTACTTCGCGCCAAAAGCTTACAGATGG GAGATAATTGAAAATGGTGT??cGGGC???CATATCGACCCGTATCATcc TCCGTTTGGAGATGCGTTGAAGACAGCACAGGAATGTATAGTTCTACCTC GGATACTGCATCAGCCACAATGGCTGATTTTTTTCAGAAATGCAAGGAGG CATTTGTAGCTTTAGCAGTICGTCCAAGAccTGGTGTTTGGGAATACGTG ACCCGAGTTATTGGTTCAAGATATCTGAAGCAGGGCTTAAAAGAATATAT CGCGTGGATGCATATCAACTAAGTGTGGAACAACTAACTGTTTCAGAGTA GAAAGGTACACATGGAAAATTTACTCTGAACGGTTGATGACATTAGCTGG TCTTACCTTCAAAGAAGAACTTGTTGGAGAGTCTAATAGTTCTTTAATGC AGTTTATAGCTTCTGGAAGTATGTCTCGAAACTTGAGAGACGTGAAACAA ?cGAGTTGGATTTTGAGCCATTTAATGCTTCGTTTccTAGACCAAC?CGT GACGATATCTTGAGATGTTTTATATTCTTAAGTTCCGTGATCTGGTAAAA TCTTCATCCATTGGCAATGGAGTTCAGTTCCTGAATCGCCACCTGTCGTC TCTGTTCCAGTGGCTACTGATGATGAGGCTTAG AAGCATGTTTCGCAGCAAAGATTGTTTAGAACCGC????GGATT?????? ( encodes SUS3 isoform ) SEQ ID NO : 20 GCACACACAGACATAATGGACATGTAATGATGTTAAATGACCGCATAACA ATGGCGACACCTAAGCTTACGCGAACACCAAGCATGCGAGAGCGTCTIGA AGCATGACT?G??????????????IGGTCAAAGCAGAGGAATA?????c AGAAACTTTATCAGCTCATCGCAACGATATCGTC??????????cCAGGT TAAACTACCATCTGA?A?AGACTACTCTGAGTTTCAATATGAATTGCAAG ATGTAGATCAAGGTAAGGCCATATTGCAGCCCCACCACCTACTTGACGAA GAATGGGTTTTGAAAGAGGATGGGGAAACAATGCTGAAAGAATCATTGAG ATCGATAACTICATcGGAGATCAAAATTGccGCCAAAAGCTTGCTGATAG ATGATGCATC????????G?????cTACAAGCTccAGATcc??cCATTTT ??????cGGTGAAATccTCAAGTccGCACAGGAAGGTATAAT???????? GGAATC????cTTGCTAGAATAccTATGGTGTTTAATGTTGTT?T?TT?T CATATGTAACGCTTGCTGTTCGTCCAAGACCTGGTGTTTGGGACTTTTTG CAATACATGGCTACTTIGGGCAACCAAATGTTTTGGGTTTGCCAGATACT CGTGTGAATGTCGATGAATTGAGTGTCGACCAACTTACTGTTTCTG?GTA GGTGGCCAGATTGTATATATATTGGATCAAGTCCGTGCATTGGAAAATGA TTTAAGCTTCAAGGAGGAGCTTGTAGATGGCCAGAGTAGGAACCCGTTTG GATGC?????AAATTAAAGCACCAAGGACTGGATATCAAACCTAGGATTC TGTTGGAACTGGATCTGGAACCGTTTAATGCAACATTTccccGGATGTCA TGATTGTGACTCGGTTAATACCTGATGCAAAAGGTACTTCATGTAACCAA CGATCTTCATCCATCGGCAATGGAGTTCAGTTTCTCAACCGTCATCTCTC CGACTGGAAAGAGTCAGTGGAACTGAACACACACATATACTTCGTGTTCC GTCAATTATGTTTCGCAACAAAGATTGTATGGATCCGTTTCTTGATTTCC TTTTAGAACCGAGAAAGGAATTCTTCGTAAATGGATCTCAAGGTTTGATG TTCGTGCTCATAAACATAAAGGATACGCGATGATGTTGAATGATCGGATA TATGGCCTTTTTTGGAGAAATTTACACAGGATGCAGCAAGTGAAATTTCT CAAACAATGTCTAGACTTGAATCTICTTTAGCAAAAGCGGAGGATCATCT GCTGAGTTGCATGGTACTCCAGATCTTATAATTGGAAATTATAGTGATGG CTCTAAACTACCACCCGAAACACCGTACTCCGAATTCGAATACGTATTGC CAATCTTGTTGCCTCTTTATTATCTTACAAAATGGGAGTAACCCAGTGTA AAGGAATGGGGTTTGAAAGAGGTTGGGGGGATAATTGTGAAAGAGTTCTT ACATTGCTCATGCTTTAGAGAAAACAAAGTATCCAGATTCTGATTTATAT GGTATGATGCATc??????cTG?????c?????????CAGATcc??cGAT TGGAAGAAATTTGATGAGAAATATCACTTTTCTTGTCAATTTACTGCTGA TCTTGAAAAGTTTCTTGGAAAGATGCCGATGATCTTCAATGTTGTTGTGT TCTTTTAGCCATGAACAATGCAGATTTTATCATCACCAGCACATACCAAG TATCGATTCATGGTTACTTTGGTCAGGCTAATGTTTTGGGTTTGCCGGAT AAATCGCGGGAACGAAAAATACTGTCGGACAATACGAGAGTCATTCGTCT ACCGGTGGTCAGGTTGTATATATATTGGATCAAGTACGTTCTTTGGAGAA ??????c?cccGGGGCTC?AcAGGGTTGTTCATGGTATTGACGTTTTTGA TGAAATGTTACTTAAATTAAGGCATCAAGGACTTGATATCAAACCCAAGA cccTAAGTTCAACATTGTGTCTccAGGGGCAGATATGT C??????????? TTCTAATTGTAACTCGATTGATACCAAATGCCAAAGGTACTTCATGCAAC CATACACCGAGAAGGAAAAAAG??????????????????????ATTGAG CAACGATTGGAGAAAGTAAGTGGAACCGAATACACGTATATATTACGTGT AAGTTATTGTTTGACCCTACACAAACTGAAGATTACATTGGAAATCTGAG CCCTTTTAGGACAGAGAAAGGGATTCTTGGTAAATGGTTATCAAGGTTTG TGATAAATCAAAACCGATAATTTTTTCAATGGCAAGACTTGATCATGTGA ATATATGGCCTTATTTGGAGGCGTTTACAACGGATGCAGCAAGTGAAATT AGAACATTACGGGTCTGGTTGAGTGGTACGCTAAGAATGAGAAGCTTAGA GCTGCTGAGTTACACGGTGTTCCGGATCTTTTAATAGGAAACTACAGTGA US 2018 /0264122 A1 Sep . 20 , 2018 39

- continued - continued TGGGAATCTCGTTGCCTCCTTGCTATCTAACAAATTGGGCGTAACCCAGT AGCTTAGATTCAAAGAATGGGGATTTGAGAAGGGATGGGGAGATAACGCG GCAACATTGCACACGCGTTAGAGAAAACAAAGTATCCAGATTCCGACTTA GAACGCGCGAGGGAAACAATTCGGTTTCTTTTGGAGGTTCTTCAAGCACC TATTGGAAGAAATTTGAGGACAAATATCACTTTTCATGTCAATTTACCGC CGATccGATAAAccTCGAGGCTTTATICAGCAGGATTcCAAACATATTCA CGACCTTCTAGCAATGAACAATGCAGATTTTATCATCACTAGCACATACC AcGTTGTTTTATTc?cGATICATGGGTATTTTGGTCAATCCAATGTTc?? AAGAGATTGCAGGAACGAAAAACACCGTTGGACAATACGAGAATCATTCA GGATTGCCCGATACTGGTGGCCAAGTGGTTTATGTTTTGGATCAAGTGGT ?cGTTCAc????ccGGGTC?A?A?AGGGTTGTTCAcGGTATCGATGTCTT AGCTATGGAAGAAGAACTACTCATGAGGATCAAACAACAAGGACTCAACT TGACCCGAAGTTCAACATCGTGTCACCAGGGGCAGATATGGCAATTTACT TCAAGCCTCAAATTCTTGTGGTGACCCGACTTCTTCCTGATGCTAAAGGG ???CATATGCCGATAAAGAGAGACG????????????????????????? GAGAAGCTATTGTTCGACACTGAGCAGAACGATGTACACATTGGAAATAT ACCAAGTGTAATCAGGTGTTGGAACCAGTTCTGAACACGAAACATTcGCA AAATGACCCGTCTAAACCCATGATTTTCACAATGGCGAGGCTTGATCATG TATTCTTAGGGTTCCATTCAGGA?TGATAAAGGTGTTCTTCGTAAATGGG TGAAGAATATAACTGGATTCGTCGAGTGTTATGCTAAAAATAATAAGTTG TATCTCGATTTGATATCTATCCATATCTCGAAAACTTCACTCAGGATGCA AGGGAACACGCAAATCTTGTGGTTATTGCTGGTTATAATGACGCGAAGAA AGTGCGAAAATCATTGAAATGATGGAAGGGAAACCGGATCTTATCATCGG ATCAAGTGATCGAGAAGAAATTGCGGAAATTGAAAAGATGCATAATCTTA AAACTATACCGATGGAAACCTTGTTGCATCACTCATGGCTAACAAACTCG TCAAGCAATACAAACTTGATGGTCAGATGAGATGGATATCAGCCCAAACA GAACGACATTGGGAACAATTGCACATGCTTTGGAGAAAACCAAATACGAA AACCGGGCCCGAAATGGGGAATTTTATCGGTATATCGCTGATGGTAGGGG GATTCAGACATGAATTGGAAGCAATTCGACCCAAAATATCACTTCTCCTG CGTTTTCGTcCAccccccTTTCTATGAAGCATTTGGGCTTACGGTTGTGG AGGCGATGACATGTGGGC??cCAACATTTGCCACGTGTCATGGTGGGCCT CCAATTTACAGCCGATATGATTGCAATGAACTCAGCTGATTTCATCATCA CAAGTACTTTCCAAGAAATCGCTGGAAGTAAAGATAGACCCGGACAATAT GCTGAGATCATTGAGGATGGTGTGTCGGGGTTCCATATTGATCCATATCA ?ccTGATAAGATGTCGACTACGTTAGCTGATTTTTTTCAAAAGTGCAAAG GAAAGCCATGAAGCATTTACACTTCCAGGATTATACAGAGTTGTTTCAGG AGGAACCTAGTTACTGGGGTAAAATATCCGATGGCGGGCTGAAAAGAATA CATCAACGTGTTcGATccCAAATTCAATATCGCGTCTccAGGAGccGATC AGTGAAAGGTACACATGGAAGATATATTCGGAACGGTTGATGACGTTGGC AAACCGTTTATTTcccGTACACCGAAACAAAGAAACGATTCACTGCATTT GGGCGTATATAGCTTTTGGAAATATGTGTCAAAACTCGAGAGGCGTGAAA CAACCCGCCATAGAGGAATTACTCTTCAGTAAAGTTGAAAACGAAGAACA cccGTCGATACCTTGAGATGTTCTACATTTTAAAGTTTCGTCAACTGGTG CATTGGATACTTAGAAGACAAAACCAAACCGATCATATTCTCAATGGCGC AAGTCGGTTCCGCTAGCTGTTGATGAGGAGCCGTAA GTCTCGACACAGTTAAGAACATAACAGGACTAACCGAATGGTTTGGAGAG ( encodes SUS4 isoform ) SEQ ID NO : 22 AACAAACGGCTCCGAAGCTTGGTTAATCTTGTAATCGTGGCGGGTTTCTT ATGGCATCTGCTTCAAGTTCTATCATGAAACGGTCTGAATCAATAGTTGA CACCATGCCAGAAGCCTTAAAGCAGAGCCGCTATCATATGAAAAAATGTT TGACCCGTCAAAGTCAAAAGACAGAGAAGAAATGGCGGAAATAAAGAAAA TTCTAAAATATGTAGAAAAAGGAATTCGCATGATGAAAAGACATCATTTG TGCATTTATTGATTGAAAAATATCAGCTTAAAGGTCAAATAAGATGGATT

ATACAAGAAATGGAGACCGCAATTGAAGACAAGGATGAAAAGGCT CAGCT GCTGCACAAACTGATAAGAACCGAAACAGTGAGCTTTACCGGTTTATTGC ????G?TGGCTTACTIGGCTACATCTTGTGCACAACTCAGGAAGCAGCCG TGACTCAAAAGGCGCGTTTGTGCAGCCCGCTTTGTATGAGGCGTTTGGGC ?TG?????????GTGTTGCATTTGCTATAAGACCGAATCCTGGATTcTGG TCACGGTTATTGAGGCGATGAACTGTGGTTTACCGACTTTTGCAACTAAT

GAGTTTGTTAAAGTCAACTCTAATGATCTATCGGTTGATGGGATAACTGC CAAGGTGGTCCAGCTGAGATTATCGTTGATGGTGTTTCTGGGTTCCAGAT CACAGATTACTTGAAGTTCAAGGAAATGATCGTAGATGAGACATGGGCTA TGATCCTAATTTTGGTGATCAGTCTAGTAATAAGATTGCTGATTTCTTCC AAGATGAAAATGCATTGGAGATTGACTTTGGATCGATGGACTTTAACCTA AGAAGTGTAAGGAAGATCCTGGTTATTGGAATAATATTTCAGAAGGCGGT CCAAACATGAGTTTATCTTGTTCGATTGGAAATGGTGTTAACTTCACATC AAAATTCATTACTTGTAAACTTTACGCACAATCTAGTTGcCAACAACTGC TTGAAGCGTATATACGAATGTTATACTTGGAAGATTTATGCGAATAAAGT TTGTTGATTACTTGC???CATTGAATCATCAAGGAGAAAATCTTATGATC GTTGAATATGGGGAACATATACTCGTTTTGGAAGCGGTTAAACAAGGAAC AATGATGCATTAAACTCAGTCTCAAAACTTCGAGCGGCTTTAATTGTAGC AAAAAGAAGCAAAACAAAGATACATTGAAC???????????????????? ?CATGCGTcGc??????cGTTGccCAACG?????cCATATCAAAcc??cG AAGAACTIGGTTAGGACTGTACCAATTGCTAGTGATGAAGCTCAACCTGC US 2018 /0264122 A1 Sep . 20 , 2018 40

- continued - continued ACCAGTGTCAAGGGCAAAACTTGCAACACAACCCACAAGACGTACGCAAT GAAAACAAGCGGTTAAGAAGTTTGGTTAATCTTGTAATTGTGGCGGGGTT CCAGGTTGCAAAGGCTGTTTGGAGCTTAA TTTTGATCCGTCAAAATCAAAAGATAGAGAAGAAATGGAAGAAATAAAGA ( encodes SUS5 isoform ) AAATGCATTTGTTGATTGAGAAATATGAACTTAAAGGTCAAATAAGATGG SEQ ID NO : 24 ATGGCAGCTICTICAAGTccCATTATGAAACGGTCTGAGTCAGTACTCGA ATAGTAGCACAAACTGATAAAAACAGAAATAGTGAACTTTATCGTTGTAT CACCATGCCAGAAGCTTTGAGGCAAAGTCGGTATCATATGAAAAAATGCT CGCTGACTCAAAGGGGGCGTTTGTGCAACCGGCTTTATATGAAGCGTTTG TTCTAAAATATGTAGGGAAAGGAAAGCGGATGGTGAAACTCCACCATTTG GGTTAACCGTTATTGAGGCTATGAATTGTGGGTTACCAACTTTTGCAACT ATGCAAGAAATGGAGACCGTCATTGAGGACAAGGACGAAAAGGCTCAGCT AACCAAGGTGGTCCGGCTGAGATTATTGTTGATGGTGTTTCTGGGTTCCA CTTGGAAGGCTTACTTGGTTACATCTTGTGCACCACTCAGGAAGCAGCAG AATCGATCCTAATTATGGCGACGAGTCTAGCAACAAGATCGCTGATTTTT TTGTTCCTCCTTATGTCGCCTTTGCAATAAGGCCAAACCCTGGATTTTGG TTCAAAAATGCAAACAGGATCCAGGATACTGGAATAGGATTTCAGACGGT GAGTTTGTTAAAGTCAACTCTAATGATCTCTCGGTTAAAGGGATCACTTC GGTTTGATGCGTATATACGAATGCTACACATGGAAGATTTATGCAAATAA CACCGATTACTTGAAGTTCAAGGAAATGATCGTTGACGAAACATGGGCTA AGTGTTGAATATGGGGAACATTTACACATTTTGGAAGCAGTTAAACAAGG ATGATGAAAATGCATTGGAGATCGACTTTGGAGCAATGGACTTTAACTTG AACAGAAAGATGCGAAACAAAGATACATTGAGCTATTCTACAATCAACAT CCAACAATGAGCTTATCTTCTTCAATTGGAAATGGAGTTAACTTCACATC TACAAGAATTTGGTTAGGACTGTGCCGATTGTAAGTGATGAAGATGACCA AAAGTTTATTATTTCTAAACTTTATGCTCATTCTGGCAGCCAATTACAAT AGTTACAAGGGCAAAACCGGCAACACAACCTICAACAAGGCGCACACAAT CTCTAGTTGATTACTTACTTTCATTAAATCATCAAGGAGAAAAACTTATG CTGCCTTGCAAAGGCTGCTTGGAGCTTAA ATAAATGACAAACTAAACACAGTTTCAAAACTICAAGCCGCTCTAATAGT ( encodes SUS6 isoform ) SEQ ID NO : 26 AGCTCATTCTTTCCTTTCTTCATTGCCCAACGACACACCGTATCAAAGCT ATGGATTTCGGTATAGCAGAGACTTTGGCCGAGGCATTGAAGCAAAACCG TTGAACTTAGATTTAAAGAGTGGGGTTTTGAAAAAGGATGGGGAGATTAT GTACCATGCAAGGAGATGCTTTGAGCGTTTTACATCACGTGGAAAAAGGA GCAGAAAGGGTGCAAGAAACAATTCGGTTTTTGTTGGAGGTTCTTCAAGC TGGTGAAGCCTCAAGAGTTATTACACATGATTGAAAAAACCATTGACGAC ACCCGACCCCGTAAACCTAGAGGCCTTTTTTAGCAGGGTTCCAAACATAT AAGCTTGAAAGAACGAAGGTCTTGGAGGGCTCAATGGGACAAATCTTGAG ?CAATATTGTTTTATTc?cGATTCATGGGTATTTTGGTCAATCCAATGTT TTCCACACAGGAGGCAATCGTTATTCCACCATATGTTATTTTAGGATTGA CTTGGCTTGCCCGATACCGGAGGTCAGGTAGTTTATGTTTTGGATCAAGT GAGCGAATCCAGGACAATGGGCATACGTTAAGATCAATGCTGATGACGTC TGTGGCAATGGAAGAAGAATTGCTACTTAGGATTAAGCAACAAGGACTCA ACTGTTGAGTCACTCACACCTTCACAATATCTAAAGTTCAAAGAATCCAT GCTTCAAGCCTCATATTCTTGTGGTGACTCGACTTCTTCCCGATGCCAAA CTACGATCAAGAATGGGCAAAGGACGAAAATGCCCTTGAACTAGATTTCG GGGACCGAGTGTAGCCAAGTTTTGGAACCAGTTCTCAACACGAAACACTC GAGCGTTCGACTTTGATACGCCTCGATTAATCCTCCCGTCATCTATCGGC ACACATTCTTAGAGTCCCATTTAGGACAGAAAAAGGTGTTCTTCGTAAAT AACGGACTCGGTTACATTTCAAAGTTCATGACTTCAAGAATTGGTGGTGA GGGTGTCTCGATTTGATATCTATCCATACCTCGAAAAGTTTACTCAGGAT TCTAGAAAACGCGAAGCCGTTGCTTGACCACTTGCTTGCTCTAAAATATC GCAAGTGCAAAAATAACTGAAATGATGGAAGGAAAACCTGATCTTATCAT ATGGAGAGAAGCTTATGATCAATGAGACAATAGATACAGTTTCAAAGCTC TGGAAACTACACTGACGGAAACTIGGTTGCATCTCTCATGGCTAACAAAC CAGAAAGCATTAATTGTTGCTGATGTCTACTTATCTGCACACCCGAAAGA TCGGAAGCACATTGGGAACGATTGCACACGCGTTAGAGAAGACTAAATAC CGAACAATATCAAACCTTAGAGCCCAAGCTTAAAGAATGGGGATTTGAGA GAAGATTCAGACATGAAATGGAAACATTTGGACACAAAATATCACTTTTC AAGGATGGGGAGATACTGCTGAAAGAGTTAGAGAGACAATGAAAATGCTT TTGTCAATTTACAGCTGATATGATAGCAATGAATTCAGCAGATTTCATCA ?cGGAGATTCTICAAGCAcccGAcccGATTAACATGCAATCGTICTTTAG TCACTAGTACTTTCCAAGAAATTGCTGGAAGTAAAGATAGACCCGGTCAG CAGGC??ccGGTGGTCTICAATATTGTCATATTTTCTATTCATGGGTATT TATGAAAGCCATGAAGCATTTACACTCCCGGGTTTATATAGAGTTGTTTC TTGGTCAATCAGATGTTCTTGGATTACCTGATACCGGAGGGCAGGTTGTT GGGCATCAAcGTGTTTGATC?CAAATTCAACATTGCATCTccGGGAGCTG TACATTCTTGATCAAGTTAAAGCATTAGAGGAAGAGATATTGCTAAGAAT ATCAAAccGTTTATTTcccTTACACGGAAACACCAAAACGATTCACTACT AAAAATGCAAGGATTGAATGCAAACCCTCGGATTCTTGTGGTGAGTCGAC ???????ccGC?A?ACAAGAATTACTCTTTAGTAAAGTTGAAAACGACGA TCATTCCCGACGCACAAGGAACAAAGTGTAACGAGGAAATGGAACCGATC ACACATTGGATATTTAGAAGATAAGAATAAACCAATCATCTTCTCAATGG TTGAACACAATGCATT???????cc??cGGGTTccTTICAGAAccTCAAA CAAGACTCGACATGGTTAAGAACATAACGGGGCTAACCGAATGGTTTGGG AGGCGTTGTTCCTCAATGGGTATCGCGGTTTGACATCTACCCGTATCTTG US 2018 /0264122 A1 Sep . 20, 2018

- continued that overall sequence identity or similarity may be less than 50 % but regions of the enzyme ( such as the catalytic site or AAAGATTcTCACAGGACGCTGCCTCTAAAATACTTGAAGTAATGGAATGT areas adjacent to the catalytic site ) may have conserved amino acids. For example, there are conserved amino acids AAACCAGATCTCATACTIGGAAACTACACAGATGGAAACATTGTTGCATC at the opening adjacent to the UDPG catalytic site . In ACTTATAGCCAAAAAGTTTGGAGTAACACAGGGGACGATTGCACACGCGT particular, a leucine at position 379 of UGT76G1 is con served . In certain embodiments , the nucleic acid encodes an TAGAGAAGACAAAGTACGAAGATTCGGATGTTAACTGGAAAAACTTTGAA UDP - glucosyltransferase having the sequence SDFGLDQ at AAAAAGTATCATTTCTCATGTCAATTTACCGCGGATTTGATCTCAATGAA a position corresponding to amino acid residues 375 to 381 of the UGT76G1 set forth in SEQ ID NO : 1 . CGCTGCAGATTTCATAATCACAAGCACTTATCAAGAAATTGTGGGAAGCA [0186 ] In certain embodiments , fragments are at least 10 , AACAAAGACCCGGACAGTATGAGACCCACGGGGCGTTTAGTATGCCCGGA at least 20 , at least 50 nucleotides in length . The fragments may be used , for example , as primers or probes. ?TTTGTAGAGTCGTGTcGGGCATCAACGTGTTTGATCCTAAGTICAACAT [0187 ] Also provided are nucleic acids that hybridize to TGCTICAcccGGTGCGGAACAATCGGTTTATTTTccGTACACCGAGAAGG the nucleic acids of the present invention or the complement thereof . In certain embodiments , there is provided a nucleic AGAAACGGTTAACGGATTTTCATC?CGCAATTAAAGAACTACT??????? acid that hybridizes to any one of the sequences set forth in SEQ ID NOs: 2 , 4 , 6 , 8 , 10 , 14 , 16 , 18 , 20 , 22 , 24 , 26 , 28 , 30 , GAACAAGACAATGACGAGCATATGGGATACCTCGCGGATGTAACCAAACC 32 and 34 or the complement thereof under conditions of GATAATATTCTCAATGGCGAGGCTCGATACGGTGAAGAACATAACAGGGT low , moderate or high stringency . A worker skilled in the art readily appreciates that hybridization and the strength of TAACCGAGTGGTTCGGTAAGAACAAACGACTTAGAAGTCTTGTAAACTTG hybridization ( i. e ., the strength of the association between GTTGTTGTCGCGGGGTTCTICGATCCATCAAAATCTAAAGACCGTGAAGA the nucleic acids ) is impacted by such factors as the degree of complementary between the nucleic acids, stringency of GATGGAGGAAATCAAGAAAATGCATGAACTAATAGAGAAATACAAACTCA the conditions involved , the Tm of the formed hybrid , and the G : C ratio within the nucleic acids. Such a worker could AGGGTCAGATGAGATGGATCGCGGCTCAAAACGATAGGACCCGCAATGGT readily determine appropriate stringent ( see, for example , GAATTGTATCGGTGTATTTCCGATACGAAGGGAGCGTTTGTGCAGCCCGC Sambrook , et al. , Molecular Cloning : A Laboratory Manual, 2nd ed . , Cold Spring Harbor Laboratory Press , New York GTTGTATGAGGCTTTTGGGCTCACGGTTATCGAGGCAATGAACTGCGGTC (1989 ) pp . 9 .50 -51 , 11. 48 -49 and 11. 2 - 11. 3 ) . TCCCGACTTTTGCAACCAATCAAGGCGGGCCCGCGGAGATCATAGTTGAC [0188 ] Typically under high stringency conditions only highly similar sequences will hybridize under these condi GGAGTTTCGGGATTTCATATTGATCCCGTTAACGGAGATGAATCAAGCAA tions ( typically > 95 % identity ) . With moderate stringency CAAGATTGCTGATTTCTTCACGAAATGCAAAGTCGATGGCGAGTATTGGG conditions typically those sequence having greater than 80 % identity will hybridize and with low stringency conditions ACCGCGTGTCGCAAGCGGGACTICAACGTATTTACGAGTGCTACACATGG those sequences having greater than 50 % identity will hybridize . AAGATGTATGCTAACAAAGCATTGAACATGGGTTCGATGTATGGTTTTTG [01891 . A non - limiting example of “ high stringency con GAGGCAATTAAACAAAGAAACTAAGCAAGCGAAGCAACGATACATCGATA ditions ” when used in reference to nucleic acid hybridization comprise conditions equivalent to binding or hybridization TCTTGTATAACTTACAATTCAAGAATTTGGCAAAAACCATTGAAATCCCT at 42° C . in a solution consisting of SXSSPE (43 . 8 g / l Naci, GATTTTGTG???ccTAAACTICAAGAACCGGTCAAAACCGAACCAACAAA 6 .9 g/ 1 NaH _ PO _H20 and 1. 85 g /1 EDTA , pH adjusted to 7 .4 with NaOH ), 0 . 5 % SDS , 5xDenhardt 's reagent and 100 ACCATTACAAGAAGCAAGACCTCGAGAACCGGTGCAAAAACTGGTACCGG ug /ml denatured salmon sperm DNA followed by washing in AAGAAACCCGACTGCCAAAACTAGAGTTGACCAAGCTTGGTCAACCGAAT a solution comprising 0 . 1xSSPE , 1 . 0 % SDS at 42° C . when a probe of about 500 nucleotides in length is employed . A TTGATGAGCAATGCAAGAAAACCATTGATTGTTCTTGTTTCTGTGTTGAT non - limiting example of " medium stringency conditions” when used in reference to nucleic acid hybridization com AGTTGCATATGCATCCAAGAACTTGTATAGGAGGTATTTCAAATAG prise conditions equivalent to binding or hybridization at 42° C . in a solution consisting of SXSSPE (43 . 8 g / 1 NaCl, 6 . 9 g / 1 [0184 ] In other embodiments, there is provided a nucleic NaH ,PO H , 0 and 1. 85 g /1 EDTA , PH adjusted to 7 . 4 with acid comprising a sequence having at least 50 % , 55 % , 60 % , NaOH ) , 0 . 5 % SDS , 5xDenhardt ' s reagent and 100 ug /ml 65 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , denatured salmon sperm DNA followed by washing in a 99 % or 100 % identity to any one of the sequences set forth solution comprising 1 . 0xSSPE , 1 . 0 % SDS at 42° C . when a in SEQ ID NOs: 2 , 4 , 6 , 8 , 10 , 14 , 16 , 18 , 20 , 22 , 24 , 26 , 28 , probe of about 500 nucleotides in length is employed . A 30 , 32 and 34 and fragments thereof or the complement non - limiting example “Low stringency conditions ” when thereof. used in reference to nucleic acid hybridization comprise [ 0185 ] In other embodiments , there is provided a nucleic conditions equivalent to binding or hybridization at 42 .de acid encoding a polypeptide comprising a sequence at least gree . C . in a solution consisting of SXSSPE (43 . 8 g / l NaC1, 50 % , 55 % , 60 % , 65 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 6 . 9 g / l NaH PO _ H20 and 1 .85 g / 1 EDTA , pH adjusted to 7 .4 96 % , 97 % , 98 % , 99 % or 100 % percent identity to any one with NaOH ) , 0 . 5 % SDS , 5xDenhardt ' s reagent and 100 of the sequences set forth in SEQ ID NOs: 1 , 3 , 5 , 7 , 9 , 13 , ug/ ml denatured salmon sperm DNA followed by washing in 15 , 17 , 19, 21, 23 , 25 , 27 , 29 , 30 , 31 and 33 and fragments a solution comprising SXSSPE , 0 . 1 % SDS at 42° C . when thereof. A worker skilled in the art would readily appreciate a probe of about 500 nucleotides in length is employed . US 2018 /0264122 A1 Sep . 20 , 2018

[0190 ] The polynucleotides include the coding sequence example , other members of the UGT91clade such as polypeptide, in isolation , in combination with additional UGT91D1 or UGT91D2. Accordingly, in certain embodi coding sequences ( e . g . , a purification tag , a localization ments, there is provided an Os03g0702000 comprising an signal, as a fusion -protein , as a pre -protein , or the like) , in amino acid sequence as set forth in SEQ ID NO : 9 or combination with non - coding sequences ( e . g . , introns or fragments and variants thereof. In certain embodiments , inteins, regulatory elements such as promoters ( including there is provided an Os03g0702000 encoded by the nucleic inducible promoters , tissue - specific promoters ( such as root acid molecule comprising the sequence as set forth in SEQ specific or leaf specific promoters ) , enhancers, terminators, ID NO : 10 . and the like) , and/ or in a vector or host environment in which [0197 ] In certain embodiments , there is provided an the polynucleotide encoding a transcription factor or tran UGT91 D1 comprising the amino acid sequence as set forth scription factor homologue polypeptide is an endogenous or in SEQ ID NO : 31 or fragments and variants thereof . In exogenous gene . certain embodiments , there is provided an UGT91 D1 [ 0191 ] Appropriate additional coding sequences ( e . g . , a encoded by the nucleic acid molecule comprising the purification tag , a localization signal, as a fusion - protein , as sequence as set forth in SEQ ID NO : 32. a pre - protein , or the like) , non - coding sequences ( e . g . regu [0198 ] In certain embodiments , there is provided an latory elements such as promoters (including inducible UGT91D2 comprising the amino acid sequence as set forth promoters , tissue - specific promoters ( such as root- specific in SEQ ID NO : 33 or fragments and variants thereof. In or leaf specific promoters ) , enhancers , terminators , and the certain embodiments, there is provided an UGT76G1 like ), and vectors for use in prokaryotic such as E . coli and encoded by the nucleic acid molecule comprising the eukaryotic cells , including but not limited to yeast and plant sequence as set forth in SEQ ID NO : 34 . cells are known in the art. [0199 ] In certain embodiments , there is provided a Stevia Polypeptides rebaudiana UGT74G1. Accordingly, in certain embodi ments, the UGT74G1 comprises the amino acid sequence as [0192 ] The present invention provides for glycosyltrans set forth in SEQ ID NO : 13 or fragments and variants ferases. The glycosyltransferases of the present invention thereof . In certain embodiments , the UGT74G1 is encoded are capable of primary , secondary and /or tertiary glycosy by the nucleic acid molecule comprising the sequence as set lations. In certain embodiments , the glycosyltransferases are capable of primary, secondary and tertiary glycosylations. In forth in SEQ ID NO : 14 . other embodiments , the glycosyltransferases are capable of [0200 ] In other embodiments , the invention provides for a secondary and / or tertiary glycosylations. In certain embodi cyclodextrin glucanotransferase . Cyclodextrin - glucano ments , the glycosyltransferases is a glucosyltransferase , transferase is commercially available (CGTase , Toruzyme including but not limited to a UDP- glycotransferase . The 3 . 0L , trademark of Novozymes Inc . ). glucosyltransferases include but are not limited to a Stevia [0201 ] In certain embodiments, there is provided sucrose rebaudiana UDP - glucosyltransferase, such as UGT76G1 or synthase . Accordingly , in certain embodiments , the sucrose UGT7461 or an Oryza sativa glucosyltrasferase , such as synthase comprises the amino acid sequence as set forth in Os03g0702000 . In other embodiments , the invention pro SEQ ID NO : 15 , 17 , 19, 21 , 23 or 25 or fragments and vides for a cyclodextrin glucanotransferase . Also provided variants thereof. In certain embodiments , the polypeptide are sucrose synthases . comprises an amino acid sequence encoded by the nucleic [0193 ] In certain embodiments , there is provided an acid molecule comprises comprising the sequence as set UGT76G1 or UGT76G1- like glucosyltransferase . forth in SEQ ID NO : 16 , 18 , 20, 22, 24 or 26 . UGT76G1- like glucosyltransferase include for example , [0202 ] In other embodiments , there is provided a poly othermembers of the UGT76G1 clade such as UGT76G2 or peptide comprising a sequence at least 50 % , 55 % , 60 % , UGT76H1. Accordingly , in certain embodiments , there is 65 % , 70 % , 75 % , 80 % , 85 % , 90 % , 95 % , 96 % , 97 % , 98 % , provided an UGT76G1 comprising the amino acid sequence 99 % or 100 % percent identity to any one of the sequences as set forth in any one of SEQ ID NOs: 1 , 3 , 5 and 7 or set forth in SEQ ID NOs: 1, 3, 5 , 7 , 9 , 13 , 15 , 17, 19 , 21 , 23 , fragments and variants thereof. In certain embodiments , 25 , 27 , 29 , 31 and 33 and fragments thereof. A worker there is provided an UGT76G1 encoded by the nucleic acid skilled in the art would readily appreciate that overall molecule comprising the sequence as set forth in any one of sequence identity or similarity of related enzymes may be SEQ ID NOs : 2 , 4 , 6 and 8 . less than 50 % but regions of the enzyme ( such as the [0194 ] In certain embodiments , there is provided an catalytic site or areas adjacent to the catalytic site ) may have UGT76G2 comprising the amino acid sequence as set forth conserved amino acids and therefore the related enzymes in SEQ ID NO : 27 or fragments and variants thereof. In have similar activity . For example , there are conserved certain embodiments , there is provided an UGT76G1 amino acids at the opening adjacent to the UDPG catalytic encoded by the nucleic acid molecule comprising the site . In particular, a leucine at position 379 of UGT76G1 is sequence as set forth in SEQ ID NO : 28 . conserved . In certain embodiments , the nucleic acid encodes [0195 ] In certain embodiments , there is provided an an UDP - glucosyltransferase having the sequence SDF UGT76H1 comprising the amino acid sequence as set forth GLDQ at a position In certain embodiments , fragments are in SEQ ID NO : 29 or fragments and variants thereof. In at least 10 , at least 20 , at least 50 amino acids in length . In certain embodiments , there is provided an UGT7661 certain embodiments , the polypeptide sequences contain encoded by the nucleic acid molecule comprising the heterologous sequences including but not limited to purifi sequence as set forth in SEQ ID NO : 30 . cation tags such as a HIS tag . In a certain embodiments , [0196 ] In certain embodiments , there is provided an there is provided a polypeptide comprising a 6xHIS tag at Os03g0702000 or Os03g0702000 - like glucosyltransferase . the N - terminus . In other embodiments, there is provided a Os03g0702000 -like glucosyltransferase include for polypeptide comprising a 6xHIS tag at the C -terminus . US 2018 /0264122 A1 Sep . 20 , 2018 43

[0203 ] Methods for screening the activity of glycosyl - tion of a vector, most typically an expression cassette , transferases including glucosyltransferases and cyclodextrin including a polynucleotide of the invention , standard tech glucanotransferases are known in the art . As such , a worker niques can be used to introduce the polynucleotide into cell skilled in the art could readily determine if the glycosyl or a plant. Optionally, the plant cell , explant or tissue can be transferases are capable of primary , secondary and/ or ter regenerated to produce a transgenic plant. tiary glycosylations (see , for example Dewitte et al. , J . 0209 ] In a certain embodiments , there is provided Can Biotechnol. 2016 September 10 ; 233 : 49 - 55 . doi: 10 . 1016 / j . nabis plants genetically engineered to express one or more jbiotec . 2016 .06 .034 ; Grubb et al. , Plant J . ( 2014 ) 79 , of the proteins of the invention . A worker skilled in the art 92 - 105 ; Richman et al. , Plant J . ( 2005 ) 41, 56 -67 ; Tanaka et would readily appreciate appropriate vectors and promoters al ., Plant Cell Rep . ( 1996 ) 15 , 819 - 823 ; Tanaka et al. , J . Nat. for genetically engineering Cannabis plats . For example , a Prod (1993 ) 56 ( 12 ) , 2068- 2072 . In addition , methods for tissue specific promoter , such as a secretory trichomes screening the activity of sucrose synthase are also known in specific promoter may be used such that the proteins of the the art . (Baroja -Fernandez et al ., PNAS . ( 2012 ) 109( 1 ) , invention are expressed in the same tissue that cannabinoids 321 - 326 . doi: 10 . 1073 /pnas . 1117099109 ; Barratt et al. , are produced in , namely the secretory trichomes of the plant. Plant Physiol. ( 2001 ) 127 , 655 -664 ; Huber and Akazawa , Suitable promoter elements include the promoter for the Plant Physiol . ( 1986 ) 81, 1008 - 1013 . cytosolic O - acetylserine ( thiol) lyase (OASA1 ) enzyme from Arabidopsis thaliana (Gutierrez - Alcala 2005 ) . Cells and Plants [0210 ] Transformation and regeneration of plant cells is [ 0204 ] The present invention further provides cells and now routine , and the selection of the most appropriate plants which express one or more of the polypeptides of the transformation technique will be determined by the practi present invention . The cells and plants may naturally express tioner. Suitable methods can include , but are not limited to : one or more of the polypeptides of the present invention or electroporation of plant protoplasts ; liposome- mediated have been modified to express one or more the polypeptides transformation ; polyethylene glycol (PEG ) mediated trans of the present invention . The cells may be prokaryotic or formation ; transformation using viruses ; micro - injection of eukaryotic cells and include but are not limited to , E . coli , plant cells ; micro - projectile bombardment of plant cells ; yeast such as Pichia pastoris , Stevia rebaudiana , Phytolacca vacuum infiltration ; and Agrobacterium tumeficiens medi Americana , Cannabis including but not limited to Cannabis ated transformation . Transformation means introducing a sativa , Cannabis indica and Cannabis ruderalis . nucleotide sequence into a plant in a manner to cause stable [0205 ] In certain embodiments , there is provided a cell or transient expression of the sequence . which expresses an UGT76G1 or UGT76G1- like glucosyl [0211 ] Successful examples of the modification of plant transferase ( such as UGT76G2 and UGT76H1) . Accord characteristics by transformation with cloned sequences ingly , in certain embodiments , there is provided a cell which which serve to illustrate the current knowledge in this field expresses an UGT76G1 glucosyltransferase comprising a of technology , and which are herein incorporated by refer sequence encoding the amino acid sequence as set forth in ence , include : U . S . Pat. Nos . 5 , 571 ,706 ; 5 ,677 , 175 ; 5 ,510 , any one of SEQ ID NOs: 1 , 3 , 5 and 7 . In certain embodi 471 ; 5 ,750 , 386 ; 5 ,597 , 945; 5 , 589 ,615 ; 5 , 750 , 871 ; 5 , 268 , ments , there is provided a cell which expresses an 526 ; 5 ,780 , 708 ; 5 , 538 , 880 ; 5 , 773 , 269 ; 5 ,736 , 369 and 5 ,610 , UGT76G1- like glucosyltransferase comprising a sequence 042 . encoding the amino acid sequence as set forth in SEQ ID [0212 ] Following transformation , plants may be selected NO : 27 or 29 . The cell may further express further gluco using a dominant selectable marker incorporated into the syltransferases, such as Os03g0702000 or Os03g0702000 transformation vector. Typically , such a marker will confer like glucosyltransferase ( such as UGT91 D1 and UGT91 antibiotic or herbicide resistance on the transformed plants , D2 ) and / or a sucrose synthase , such as the sucrose synthase and selection of transformants can be accomplished by comprising the sequence as set forth in SEQ ID NO : 15 , 17 , exposing the plants to appropriate concentrations of the 19 , 21, 23 or 25 . antibiotic or herbicide . [ 0206 ] Accordingly , in certain embodiments , there is pro vided a cell which expresses UGT76G1 glucosyltransferase Methods comprising a sequence encoding the amino acid sequence as [0213 ] The present invention further provides methods for set forth in any one of SEQ ID NOs: 1 , 3 , 5 and 7 and the production of cannabinoid glycoside prodrugs and the Os03g0702000 glucosyltransferase comprising the cannabinoid glycosides prodrugs produced by the methods . sequence as set forth in SEQ ID NO : 10 . The cellmay further The methods may be in vitro or in vivo (in a cell system or express a sucrose synthase comprising the sequence as set in planta ). In certain embodiments , there is provided a forth in SEQ ID NO : 15 , 17 , 19 , 21, 23 or 25 . method of producing cannabinoid glycoside prodrugs , said [ 0207 ] In certain embodiments , there is provided a cell method comprising incubating a cannabinoid aglycone with which expresses an Os03g0702000 or Os03g0702000 - like one or more sugar donors in the presence of one or more glucosyltransferase . Accordingly , in certain embodiments , glycosyltransferases. there is provided a cell which expresses Os03g0702000 10214 ] The aglycones include but are not limited to : glucosyltransferase comprising a sequence encoding the cannabinoids, including but not limited to cannabidiol, can amino acid sequence as set forth in SEQ ID NO : 10 . The cell nabidivarin , cannabigerol, tetrahydrocannabinol, cannabinol may further express a sucrose synthase , such as the sucrose and cannabidiolic acid , endocannabinoids including but not synthase comprising the sequence as set forth in SEQ ID limited to arachidonoylethanolamide (anandamide , AEA ) , NO : 15, 17 , 19 , 21 , 23 or 25 . 2 -arachidonoylethanolamide (2 - AG ), 1 - arachidonoyletha [0208 ] Transgenic cells and plants ( including plant cells , nolamide ( 1 - AG ) , and docosahexaenoyl ethanolamide or plant explants , or plant tissues ) can be produced by a (DHEA , synaptamide ) ; and vanilloids including but not variety of well established techniques. Following construc - limited to vanillin , curcumin , and capsaicin . US 2018 /0264122 A1 Sep . 20 , 2018 44

[0215 ] Aworker skilled in the art would readily appreciate transferase under conditions which allow for glycosylation . that the one or more sugar donors will be dependent on the In alternative specific embodiments , there is provided a one or more glycosyltransferases used in the method and / or method of producing a cannabinoid glycoside, said method the desired end products . For example , for UDP - glucosyl comprising incubating an aglycone with UDP - glucose and transferases , the sugar donors include but are not limited to maltodextrin in the presence of a UGT76G1 or UGT76G1 UDP - glucose , UDP - glucuronic acid , UDP -mannose , UDP like glucosyltransferase and cyclodextrin glucanotransferase fructose, UDP -xylose , UDP - fluorodeoxyglucose , and UDP rhamnose . For cyclodextrin glucanotransferase, the sugar under conditions which allow for glycosylation . Also pro donor includes maltodextrin . vided are cannabinoid glycosides produced by the above [0216 ] In certain embodiments , there is provided a method methods. of producing a cannabinoid glycoside , said method com [ 0222 ] An exemplary method for producing cannabinoid prising incubating an aglycone with a sugar donor in the glycosides comprises incubating cannabinoid , including but presence of a glycosyltransferase . Also provided are the not limited to cannabidiol, cannabidivarin , canabigerol, tet cannabinoid glycosides produced by the above method . In rahydrocannabinol, cannabinol and cannabidiolic acid , with specific embodiments , there is provided a method of pro UDP -glucose in the presence of a UGT76G1 or UGT76G1 ducing a cannabinoid glycoside , said method comprising like glucosyltransferase and Os0390702000 or incubating an aglycone with UDP -glucose , in the presence Os03g0702000 -like glucosyltransferase under conditions of a UGT76G1 or UGT76G1- like glucosyltransferase under which allow for glycosylation . Also provided are cannabi conditions that allow for glycosylation . In other specific noid - glycosides produced by the above method . embodiments , there is provided a method of producing a glycoside prodrug, said method comprising incubating an [ 0223 ] A further exemplary method for producing can aglycone with maltodextrin , in the presence of a cyclodex nabinoid - glycosides comprises incubating cannabinoids trin glucanotransferase under conditions that allow for gly with UDP - glucose and maltodextrin in the presence of a cosylation . UGT76G1 or UGT76G1- like glucosyltransferase and and [0217 ] An exemplary method for producing cannabinoid cyclodextrin glucanotransferase under conditions which glycosides comprises incubating a cannabinoid , with UDP allow for glycosylation . Also provided are cannabinoid glucose in the presence of a UGT76G1 or UGT76G1- like glycosides produced by the above method . glucosyltransferase under conditions which allow for gly [ 0224 ] It is within the scope of the present invention that cosylation . Also provided are cannabinoid - glycosides pro each of the above described glycosylation methods may be duced by the above method . applied to a lower order cannabinoid glycoside to form a [ 0218 ] A further exemplary method for producing can higher order cannabinoid glycoside . For example , a can nabinoid - glycosides comprises incubating a cannabinoid nabinoid monoglycoside may be glycosylated using any of with maltodextrin in the presence of a cyclodextrin glucano the glycosylation methods of the present invention to form transferase under conditions which allow for glycosylation . a diglycoside , or a cannabinoid diglycoside may be glyco Also provided are cannabinoid - glycosides produced by the sylated to form a triglycoside, etc. above method . [ 0219 ] In certain embodiments , there is provided a method [0225 ] Methods of purifying the cannabinoid glycosides of producing a cannabinoid glycoside, said method com are known in the art and include for example solid phase prising incubating an aglycone with one or more sugar extraction , such as column purification . donors in the presence of a first glycosyltransferase and a [ 0226 ] The invention also provides cell culture and in second glycosyltransferase under conditions which allow for planta methods for the production of cannabinoid glyco glycosylation . Also provided are cannabinoid glycosides sides . The methods comprise expressing one or more of the produced by the above method . glycosyltransferases in a cell or plant which produces the [ 0220 ] Aworker skilled in the art would readily appreciate aglycone and isolating the cannabinoid glycosides . In cer that the first glycosyltransferase and a second glycosyltrans tain embodiments , one or more sucrose synthases are also ferase may be provided concurrently or added sequentially. expressed . Appropriate vectors and genetic engineering In addition , if more than one sugar donor is used , the sugar methods are known in the art . donors may be provided concurrently or added sequentially . Such a worker would further appreciate that the structure of [0227 ] The invention also provides methods for the con the resulting cannabinoid glycoside may be dependent on version of UDP to UDPG utilizing the sucrose synthases of the order the glycosyltransferases are provided . In addition , the present invention . Accordingly , in certain embodiments the ratio of first to second glycosyltransferase may impact of the methods of producing cannabinoid glycosides which the resulting products. A worker skilled in the art would utilize UDP - glucose as a sugar donor, the methods further further appreciate that the activity levels of the glycosyl comprise the use of sucrose synthase to recycle UDP. In transferases may dictate the ratios and the ratios could be certain embodiments , there is provided a method of produc readily determined by a worker skilled in the art . For ing a cannabinoid glycoside , said method comprising incu example , the ratios first to second glycosyltransferase bating aglycone with UDP - glucose , in the presence of a include but are not limited to 1 : 1 , 1 : 2 , 1 : 10 , 1 : 50 and vice UGT76G1 glucosyltransferase and a sucrose synthase under versa . conditions that allow for glycosylation . [ 0221 ] In specific embodiments , there is provided a 10228 ]. The invention will now be described with reference method of producing a cannabinoid glycoside, said method to specific examples. It will be understood that the following comprising incubating an aglycone with UDP - glucose in the examples are intended to describe embodiments of the presence of a UGT76G1 or UGT76G1- like glucosyltrans invention and are not intended to limit the invention in any ferase and Os03g0702000 or Os03g0702000 - like glucosyl way . US 2018 /0264122 A1 Sep . 20 , 2018 45

Examples primary sugar. This additional treatment created a new category of compounds termed B - primed , a - glycosylated Example 1 : Conversion of Cannabinoids to cannabinoids. Cannabinoid Glycoside Prodrugs [0229 ] Glycosylation reactions consisted of 50 mM KPO4 Example 4 : Purification of Cannabinoid Glycosides pH 7 .2 , 3 mM MgCl2 , 0 . 005 % CBD , 2 . 5 % UGT76G1 [ 0234 ] Glycoside products were generated through the purified enzyme preparation , and 2 . 5 mM UDP - glucose . aforementioned biocatalytic reactions and purified to homo Buffers were degassed and tubes were purged with nitrogen , geneity by C18 solid phase extraction . 100 mg Hypersep reactions were protected from light and incubated at 28° C . C18 columns ( Thermo ) were hydrated in methanol, rinsed with 180 rpm agitation for 18 hours . Reactions were then with 50 % methanol in water, rinsed with water, glycosy extracted 3x with an equal volume of ethyl acetate, evapo lation reaction passed through the column , washed with rated to dryness , and dissolved in a half volume of HPLC water, washed with 10 % , 20 % , and 30 % methanol , and the grade methanol. 50 microliters was injected on a reverse glycoside products were eluted with 45 and 60 % methanol phase C18 column and eluted with a gradient of acetonitrile in water. Eluates were dried and extracted with ethyl acetate , starting at 10 % and increasing to 99 % . UGT76G1 was and dried to completion to yield > 95 % pure cannabinoid produced through expression in Pichia pastoris and purified glycosides for further analysis and testing . through standard molecular biology techniques. The UGT76G1 enzyme was found to glycosylate CBD in a Example 5 : HPLC Analysis of Cannabinoid UDP - glucose dependent manner . This activity was also Glycoside Prodrugs proportional to the amount of UDP - glucose present. Incu [ 0235 ] The HPLC linetraces of the reaction products of bation temperature was 28° C ., and an acceptable range glycosylation reactions of the cannabinoid aglycones CBD , would be 20° C . to 30° C . as high temperatures can cause CBDV, A9 - THC , CBN , 1 - AG and 2 - AG , DHEA , AEA , significant degradation of CBD . Reactions were carried out capsaicin , and vanillin , are provided in FIGS . 16 to 24 , in the dark to prevent photo - degradation of the substrates . respectively . Enzymatic reactions were performed as Gentle agitation from 120 to 200 rpm were used to mix the described in Example 1 . The solid lines indicate the elution reactions in an inert atmosphere . profile of the starting aglycone and the dashed lines indicate [0230 ] Substrate CBD in the reactions was replaced with the elution profile of the glycosylation reaction product ASTHC and CBDV and performed in an identical fashion mixture . with similar results . Enzyme combinations needed to create [0236 ] In FIG . 16 , the CBD aglycone retention time is various products are listed in Table 4 for CBD - glycosides , 13 .65 minutes, and product peaks are observed at 8 .87 , 9 .02 , Table 5 for CBDV - glycosides , and Table 6 for A9THC 9 .97 , 10 .33 , and 10 .37 min . glycosides . [0237 ] In FIG . 17 , the CBDV aglycone retention time is [ 0231 ] Other enzymes screened for activity towards CBD 12 .75 minutes, and product peaks are observed at 8 . 53 , 9 .70 , were the Stevia rebaudiana UGT74G1, UGT85C2 , UGPase , and 10 .01 min . E . coli Maltodextrin phosphotransferase (MaIP ) , and 0 . [0238 ] In FIG . 18 , the THC aglycone retention time is sativa Os03g0702000 (SEQ ID NO . 9 ) . No primary glyco 14 .45 minutes , and product peaks are observed at 9 . 46 , sylation activity was seen with any other tested enzyme 10 .67 , 10 . 97 , 11 .28 , 11 .67 , and 12 .49 min . other than UGT76G1. (0239 ] In FIG . 19 , the CBN aglycone retention time is 14 . 32 minutes, and product peaks are observed at 10 .87 , Example 2 : 2 - 0 glycosylation of of 11. 50 , and 12 .25 min . CBD -Monoglycoside 10240 ] In FIG . 20 , the 1 - AG aglycone retention time is [ 0232] Enzymatic reactions are performed as described in 14 . 18 minutes and the 2 -AG aglycone retention time is Example 1 but with the inclusion of recombinant 14 . 32 minutes , and product peaks are observed at 11 . 40 , Os03g0702000 enzyme at a 1: 2 ratio relative to UGT76G1. 11 .78 , 11 .83 , 11 .97 , 12 .53 , 12 . 92 , 13 . 07 , and 13 .35 min . Samples were extracted and analyzed as in Example 1 . [0241 ] In FIG . 21, the DHEA aglycone retention time is Recombinant Os03g0702000 enzyme was codon optimized 13 . 78 minutes , and product peaks are observed at 10 .09 and and expressed in E . coli BL21 - DE3 cells and purified by 12 . 43 min . immobilized metal ion chromatography . [0242 ] In FIG . 22 , the AEA aglycone retention time is 13 . 87 minutes, and product peaks are observed at 12 .47 min . Example 3 : Conversion of CBD to alpha - glycoside [0243 ] In FIG . 23 , the vanillin aglycone retention time is Linked CBD Compounds 1 . 95 minutes and product peaks are observed from 1 . 25 to [ 0233] Recombinant cyclodextrin glucanotransferase 1 . 35 min . (CGTase , Toruzyme 3 . 0L trade name, Novozymes Inc . ) was [0244 ] In FIG . 24 , the capsaicin aglycone retention time is added to reactions as indicated in Example 1 but without 11 .73 minutes , and product peaks are observed at 10 .23 min . UDPG or UGT76G1. Maltodextrin was used at 0 .05 % final concentration , and Toruzyme 3 .0L was used at 0 . 1 % . Example 6A : LCMS Analysis of CBD Glycosides Samples were extracted and analyzed as in example 1 . [0245 ] As shown in the HPLC linetrace of FIG . 16 , input Additionally , reactions from Example 1 were carried out to CBD aglycone ( VB101 , 13 .65 ') has been depleted to 5 % of convert cannabinoids to cannabinoid - glycosides, and then original quantity after + 65 hours of incubation time. The CGTase and maltodextrin were added and given adequate CBD - glycosides elute off the HPLC column at 8 .87 , 9 .02 , time to incubate with the cannabinoid - glycosides . The 9 .97 , 10 . 33 , and 10 .37 min . The glycosylated products were resulting products contain a B - glycosylation on the cannabi- identified by LCMS analysis . The glycosylated product “ g1" noid backbone , and a - glycosylations emanating from the is a monoglycoside , " g2” is a diglycoside, " g3 ” is a trigly US 2018 /0264122 A1 Sep . 20 , 2018 46

coside , and “ g4 ” is a tetraglycoside . LC - LRMS was per log P values (http : // pubchem .ncbi . nlm . nih . gov / ) and used to formed on a Shimadzu LC -MS 2010 EV instrument. The LC create a calibration line as depicted in FIG . 29 . The predicted column used was a Silia Chrom XDB C18 5 um , 150A , CLogP values correlated with the reference calibration line . 4 .6x50 mm . The method was 12 min 5 to 95 H , O : ACN C18 reverse phase HPLC retention times were plotted gradient. For LRMS electrospray ionization (ESI ) was per against the cLogP values presented in Table A , as depicted formed in positive mode. in FIG . 29 . Data point numbering correlates with table [0246 ] VB101 (CBD aglycone ) MS data : LC / ESI- LRMS . numbering . Open diamonds indicate novel cannabinoid gly [ M + H ] + (C21H3 , 02) Calcd : m /z = 315 . Found : m / z = 315 . cosides , filled diamonds indicate reference cannabinoids and [ 0247] ( CBDg1) MS data : LC / ESI- LRMS . [ M + H ] * derivatives . Clog P values were predicted by ChemDraw (C22H4 , 04) Calcd : m / z= 477 . Found : m / 7 = 477 . (CambridgeSoft ). Linear regression was performed on all [0248 ] VB104 (CBDg2 ) MS data : LC /ESI - LRMS . data points (R2 = 0 .9455 ) . [ M + H ] * ( C33H51012 ) Calcd : m / z = 639 . Found : m / z = 639 . 10249 ] VB110 (CBDg2 ) MS data : LC / ESI- LRMS. TABLE A [ M + H ] * (033H51012 ) Calcd : m / z = 639 . Found : m / z = 639 . 10250 ] ( CBDg3 ) MS data : LC / ESI- LRMS . [ M + H ] + CLogP values for select cannabinoid (C20H61017 ) Calcd: m /z = 801. Found : m /z = 801. [M + K + H ] * glycosides and reference cannabinoids (C22H6 61, 0 , K ) Calcd : m / z = 420 . Found : m / z = 420 . # Compound Retention Time ClogP [ M + ACN + H2O + H ] * (C41H63N017 ) Calcd : m / z = 860 . 1 VB110 8 . 967 3 . 4 Found : m / z = 860 . 2 11 - COOH - Tetrahydrocannabinol 9 . 347 3 . 7 [ 0251] (CBDg4 ) MS data : LC / ESI- LRMS. [ M + H ] * Glucuronide (C45H7 , 022 ) Calcd : m / z = 964 . Found : m /z = 964 . [ M +H20 + 3 VB104 10 . 720 H ] + (C4 H 0 , 2 ) Calcd : m / z = 983 . Found : m / z = 983 . 4 VB304 11 . 250 0252 ) (CBDg3 ) MS data : LC /ESI -LRMS . [ M + H ] + 5 VB302 11 . 688 New 6 11 - COOH - Tetrahydrocannabinol 12 .910 (C32H61017 ) Calcd : m / z = 801 . Found : m / z = 801. [M + Na] * 7 Cannabidivarin 13 .017 tininin (C2H 0 , Na ) Calcd : m / z = 823 . Found : m / z = 823 . [ M + K + 8 11 -OH - Tetrahydrocannabinol 13. 037 5 . 9 9 Cannabidiol 13. 647 6. 6 H ]2 + (C33H61017K ) Calcd : m /7 = 420 . Found : m / 7= 420 . 10 Cannabinol 14 . 178 7 . 3 Example 6B : LCMS Analysis of A9 - THC 11 Tetrahydrocannabinol 14 . 487 7. 2 Glycosides [ 0253] In a manner similar to that carried out in Example Example 9 : Bioavailability Assay 6A , the products of the glycosylation reaction of A9 - THC ( shown in the HPLC linetrace of FIG . 18 ) were identified by [0259 ] In order to investigate the effectiveness of glyco LCMS analysis . sylation to effect site - specific drug delivery , VB110 was [ 0254 ] VB301 ( THC aglycone ) MS data : LC /ESI - LRMS . administered to three mice by oral gavage and the animals [M + H ]* (C21H3102 ) Calcd : m /z = 315. Found : m /z = 315 . sacrificed at 30 , 60 , and 90 minutes. Eight week old male [ M + 3ACN + 2H ] 2 - (C22H41N202 ) Calcd : m / z = 314 . Found : Swiss mice were fasted for 12 hours prior to administration m / z = 314 . of 120 mg/ kg VB110 in 10 % Ethanol USP , 10 % Propylene Glycol USP , 0 .05 % Sodium Deoxycholate USP, 79 .95 % [ 0255 ] VB304 ( THCg2 ) MS data : LC /ESI - LRMS . Saline USP . Following termination and tissue harvest , the [ M + H ] * (C33H51012 ) Calcd : m / z = 639. Found : m / z = 639 . intestinal contents were then extracted and analyzed by C18 [ 0256 ] VB308 ( THCg3 ) MS data : LC /ESI - LRMS . reverse phase HPLC . As shown in FIG . 30A , the small M + H ] + ( C22H6, 0 , - ) Calcd : m / z = 801. Found : m / z = 801 . intestinal contents showed intact VB110 , but no decoupled [M + Na] + (C39H600 , Na) Calcd : m /z = 823 . Found : CBD . As shown in FIG . 30B , the large intestinal contents m / z = 823 . [ M + K + H ] * (C33H61017K ) Calcd : m / z = 420 . contained both VB110 and CBD in the 60 and 90 minute Found : m / z = 420 . time points . This decoupling of VB110 is consistent with the Example 7: NMR Analysis of Cannabinoid large intestinal decoupling seen for sennoside beta - glyco sides , and is the result of secreted beta - glycosidases from the Glycosides large intestinal microflora . [0257 ] FIG . 27 depicts the ' NMR spectra of isolated VB104 and FIG . 28 depicts the ' H MR spectra of isolated Example 10 : Analysis of Large Intestine Contents VB110 . Each of these products was isolated from the Upon Administration of CBD and CBD Glycosides reaction mixture produced by the glycosylation reaction of [0260 ] In order to investigate the metabolism and decou CBD . The ' H NMR spectra of 10 mg/ ml solutions of each pling of CBD - glycosides in the large intestine, an aqueous compound prepared in CD OD were obtained on a Bruker solution of a mixture of CBD - glycosides was administered Avance II 400 MHz instrument using TopSpin acquisition to a mouse by oral gavage . As a control, a solution of CBD and processing software . in cremophor, ethanol, and saline was administered to a second mouse . The animals were each sacrificed at 2 hours . Example 8: Solubility Analysis Following termination and tissue harvest , the intestinal [ 0258 ] C18 retention times were empirically determined contents were then extracted and analyzed by C18 reverse on a linear ramp of increasing acetonitrile on a Phenomenex phase HPLC . The mice employed in this example were eight Kinetex 2 .6u 100A C18 column , on a Dionex HPLC week old male Swiss mice fasted for 12 hours prior to equipped with Diode Array Detector . CLogP values in Table administration of the solutions. A were predicted by ChemDraw (CambridgeSoft ) . Refer [0261 ] The resulting extracts were analyzed by LCMS ence cannabinoids were analyzed by HPLC and established performed using a Shimadzu LC -MS 2010 EV. LC separa US 2018 /0264122 A1 Sep . 20 , 2018

tion was carried out using a Silia Chrom XDB C18 5 um , Example 11 : Analysis of Large Intestine Contents 150A , 4 .6x50 mm . The method was 12 min , 5 to 95 Upon Administration of THC -Glycosides H2O : ACN gradient elution . Low resolution MS was per [0270 ] In order to investigate the metabolism and decou formed in negative mode via electrospray ionization (ESI ) . pling of THC - glycosides in the large intestine, an aqueous Acetic acid and formic acid were used as sample additives solution of a mixture of THC - glycosides was administered during analysis , and the injection volume was 20 to two mice by oral gavage . The first animal was sacrificed [0262 ] Analysis of the large intestinal contents of animals at 2 hours and the second animal was sacrificed at 4 hours . administered a mixture of oral CBD - glycosides indicated Following termination and tissue harvest , the intestinal that both aglycone and glycosides were present, along with contents were then extracted and analyzed by C18 reverse hydroxy metabolites of each : phase HPLC . The mice employed in this example were eight [0263 ] [CBD - H ], [ 2CBD - H ] and [CBD * 20H + Formic week old male Swiss mice fasted for 12 hours prior to acid - H ] MS data : LC /ESI - LRMS . [M - H ] - (C2 H290229 ) administration of the solutions . Calcd : m /z = 313 . Found : m / z = 313. [2M - H ]- (042H5904 ) [0271 ] The resulting extracts were analyzed by LCMS Calcd : m /z = 627 . Found : m / z = 627 . [M * 204 + Formic acid under the same conditions employed in Example 10 . H ] - (C22H3106 ) Calcd : m / z = 391. Found : m / z = 391. [0272 ] Analysis of the large intestinal contents from mice administered THC glycosides after 2 hours indicated that [0264 ] [CBDg1 - H ], [CBDg1 + Cl] and [2CBDg1 - H ] MS both THC aglycone and THC glycosides were present, along data : LC /ESI - LRMS . [ M , 1 - H ] (C20H390 ) Calcd : with hydroxy metabolites of each : m /z = 475. Found : m / z= 475 . [M , 1 + Cl] - (C27H400 ,CI ) Calcd : [0273 ] [ THC - H ], [ THC * OH - H ], [2THC * 30H + Acetic m / z = 511 . Found : m / z = 511. [ 2M , 1 - H ] - (C34H2 , 014 ) Calcd : acid - H ] and [ THC * 20H + Formic acid - H ] MS data : m / z = 951. Found : m / z = 951 . LC /ESI - LRMS . [M - H ] - (C2 H2902 ) Calcd : m / z = 313 . [ 0265 ] [ CBDg2 - H ] and [CBDg2 + Acetic acid - H ] MS Found : m /z = 313 . [ M # ow - H ]- (C2H2 , 0z) Calcd : m /z = 329 . data : LC /ESI - LRMS . [ M , 2 - H ] - (C33H49012 ) Calcd : Found : m / z = 329. [ 2M * 304 + Acetic acid - H ] - (C44H63012 -) m /z = 637. Found : m / z = 637 . [Mg2 + Acetic acid - H ] Calcd : m /z = 783. 9 . Found : m /z = 783. [M * 20H + Formic acid (C35H53014 -) Calcd : m / z = 697. Found : m / z = 697 . H ] - (C22H3106 ) Calcd : m / z = 391. Found : m / z = 391. [ 0266 ] [CBDg3 - H ], [ CBDg3 * OH - H ] and [CBDg3 * OH [0274 ] [ THCg1 + Cl] , [ THCg1 + Acetic acid - H ] , 2H ] MS data : LC /ESI - LRMS. [M 3 - H ] - ( C3 , H 90 ) [2THCg1 - H ], and [2THCg1 + Acetic acid - H ] MS data : Calcd : m / z= 799. Found : m /z = 799. [M23 * 0H - H ] LC /ESI - LRMS. [ M , 1 + Cl] - (C22H400 _ C1- ) Calcd : m /z = 511. (C39H5 , 018 ) Calcd : m / z = 815 . Found : m / z = 815 . [ M , 3 * OH Found : m /z = 511 . [M 1+ Acetic acid - H ] - ( C2H430 , -) 2H ] -2 (C32H53018 ) Calcd : m /z = 407 . Found : m /z = 407 . Calcd : m / z = 535 . Found : m / z = 535 . [ 2M , 1 - H ]- (C34H7 , 014 ) Calcd : m / z = 951 . Found : m / z = 951. [ 2M , i + Acetic acid - H ] [0267 ] Analysis of the large intestinal contents of animals (C36H33016 ) Calcd : m / z = 1011 . Found : m / z = 1011 . administered oral CBD indicated that hydroxy metabolites [0275 ] [ THCg2 - H ], [ THCg2 + Acetic acid - H ] and of CBD were present: [ THCg2 * OH + Formic acid - H ] MS data : LC /ESI - LRMS . [0268 ] [CBD * 20H + Formic acid - H ] and [2CBD * 30H + [M , 2 - H ]- (C33H49012 ) Calcd : m / z = 637 . Found : m /z = 637 . Acetic acid - H ] MS data : LC /ESI - LRMS . [M2 + 04 + Formic [M , 2+ Acetic acid - H ] - (C35H53014 ) Calcd : m /z = 697. acid - H ]- (C22H310 ) Calcd : m / z = 391. Found : m / z = 391. Found : m / z= 697 . [Mg2 + on + Acetic acid - H ]- (C34H51015 ) [2M * 304 + Acetic acid - H ] - (C4H63012 ) Calcd : m /z = 783. 9 . Calcd : m / z = 699. Found : m / z = 699 . Found : m / z = 784 . [0276 ] [ THCg3 - H ], [ THCg3 + Acetic acid - H ], [ 0269] The plasma and brains from the same animals were [CBDg3 * OH - H ] and [CBDg3 * OH - 2H ] MS data : LC /ESI also extracted and analyzed by HPLC for the presence of LRMS. [ M 3 - H ] - (C39H5 , 017 ) Calcd : m / z = 799 . Found : CBD -glycosides and CBD . CBD was only present in the m /z = 799 . [M ,3 + Acetic acid - H ]- ( C41163019 ) Calcd : control animal that received CBD aglycone ( data not m / z = 859 . Found : m / z = 859 . [Mg3 * 0 - H ]- (C39H59018 ) shown ) . The contents of the small intestines from the same Calcd : m /z = 815 . Found : m /z = 815 . [Mg3 * 0H - 2H ]- 2 animals were also extracted and analyzed by HPLC for the (C20H380182 - ) Calcd : m /z = 407. Found : m /z = 107. presence of CBD - glycosides and CBD , but no CBD agly 0277 ) Analysis of the THC glycosides mixture extract cone was present in the small intestines ( data not shown , after 4 hours indicated that both THC aglycone and THC consistent with THC decoupling data shown in example 11 ) . glycosides were confirmed , along with hydroxy metabolites The presence of the CBD aglycone in the large intestinal of each : contents indicates the successful delivery of CBD - glyco [0278 ] [ THC - H ], [ THC * OH + Acetic acid - H ] , sides, and the subsequent hydrolysis of the glycosides by [2THC * 30H + Acetic acid - H ] and [ THC * 20H + Formic beta - glycosidase enzymes only present in the large intestine . acid - H ] MS data : LC/ ESI -LRMS . [M - H ]- (C2 H2, 02) The presence of decoupled CBD in the large intestine, but Calcd : m / z = 313 . Found : m / z = 313 . [ M oH + Acetic acid - H ] not in the small intestine , indicates that glycoside decou (C23H3305 ) Calcd : m / z = 389 . Found : m / z = 389 . [ 2M * 304 + pling only occurs upon transit to the large intestine . The Acetic acid - H ] - (C44H63012 ) Calcd : m / z = 783 . 9 . Found : presence of CBD detoxification metabolite CBD - 20H is m / z = 784 . [ M # 204 + Formic acid - H ] “ (C22H3106 ) Calcd : also consistent with delivery of CBD and absorption into the m / z = 391. Found : m / z = 391 . intestinal epithelium where CBD begins to be metabolized . [0279 ] [ THCg1 + Cl] , [ THCg1 + Acetic acid - H ], This example illustrates the potential to administer CBD [2THCg1 - H ], and [2THCg1 + Acetic acid - H ] MS data : glycosides, safely transit the CBD - glycosides through the LC / ESI- LRMS . [M , 1 + Cl] - (C27H400 , Cl- ) Calcd : m /z = 511. small intestine without absorption , transit to the large intes Found : m / z = 511. [ M , + Acetic acid - H ] - (C20H4200 - 42 ) tine where the sugars can be decoupled to release CBD Calcd : m / z= 535 . Found : m /z = 535 . [2Mg1 - H ] - (C34H29014 ) locally , avoiding systemic absorption and delivery of the Calcd : m /z = 951. Found : m /z = 951. [2M1 , i + Acetic acid - H ] CBD to other tissues where it can have unwanted effects . (C56H23016 ) Calcd : m /z = 1011. Found : m /z = 1011 . US 2018 /0264122 A1 Sep . 20 , 2018

[0280 ] [ THCg2 - H ] and [ THCg2 + Acetic acid - H ] MS [0285 ] Enzymatic activities were tested and assayed for data : LC /ESI - LRMS . [ M , 2 - H ] - (C33H43012 ) Calcd : their ability to enhance UGT reactions with decreased m / z = 637 . Found : m / z = 637 . [M 2 + Acetic acid - H ] UDPG input. The best isoform , SrSUS4 , was capable of (C35H53014 .) Calcd : m / z = 697 . Found : m /z = 697 . recycling UDP to UDPG with sucrose , in concert with the [0281 ] [ THCg3 - H ], [ THCg3 + Acetic acid - H ], steviol 19 - 0 - glucosyltransferase SrUGT7461 mediated [ CBDg3 * OH - H ] , [ CBDg3 * OH - 2H ] and [ CBDg3 * OH + glycosylation of steviol bioside to stevioside . Acetic acid - 2H ] MS data : LC / ESI- LRMS . [M , 3 - H ] [0286 ] Targeted mutagenesis was performed to mutate a (C33H59017 ) Calcd : m /z = 799. Found : m /z = 799 . [M 3 + Ace serine residue at the N -terminus that is commonly phospho tic acid - H ]- (C41H63019 ) Calcd : m /z = 859 . Found : rylated in planta to prevent dimerization (Hardin 2004 ) . m /z = 859. [M93 * OH - H ]- (C33H59018 ) Calcd : m / z = 815 . SrSUS1- S13D mutants were created by mutating serine at Found : m / z = 815 . [Mg3 * 0H - 2H ] -2 (C39H580182 -) Calcd : position 13 to an aspartic acid residue (S13D ) , thus forming m /z = 407. Found : m /z = 407. [M 3* OH + Acetic acid - 2H ] - 2 a phospho - mimetic protein . Additionally, the creation of (C41H6202025 ) Calcd : m /z = 467 . Found : m / z= 467. SrSus1 -S13R ,L141 was created to replace the serine with an [ 0282] The plasma and brains from the same animals were arginine, a large charged residue, also to prevent dimeriza also extracted and analyzed by HPLC for the presence of tion and inactivation of the enzyme. Sucrose synthase THC - glycosides and THC , but neither compound was seen mutants showed improved UDPG production activity com in these tissues ( data not shown ) . The contents of the small pared to their native counterparts . SrSUS5 ( SEQ ID NOs. 19 intestines from the same animals were also extracted and and 20 ) was identified in the Stevia transcriptome and analyzed by HPLC for the presence of THC - glycosides and primers designed (SEQ ID NOs. 67 and 68 ) , but was not able THC , but no THC aglycone was observed (data not shown , to be amplified from cDNA. SrSus4 showed an impressive consistent with CBD decoupling data shown in Example UDPG recycling activity with a 20 % improvement over the 10 ) . The presence of the THC aglycone in the large intestinal activity seen in SrSus1 . It is proposed that SrSus4 is the ideal contents at 2 and 4 hours indicates the successful delivery of isoform for carrying out the back reaction of converting of THC - glycosides , and their subsequent hydrolysis of the UDP to UDPG in the presence of sucrose . For midi -scale glycosides by beta - glycosidases in the large intestine . The purification of cannabinoid glycosides the use of C18 flash presence of decoupled THC in the large intestine , but not in chromatography columns were employed . Biotage flash C18 the small intestine, indicates that glycoside decoupling only columns with 33 g of resin were washed , loaded , washed , occurs upon transit to the large intestine . The presence of and eluted using peristaltic pumps to achieve the similar THC detoxification metabolites in the large intestine is separation and purification as the gravity fed Hypersep further proof that the THC aglycone is present and being columns listed previously . absorbed by the intestinal epithelium where it begins to be [0287 ] Relative activity for UDPG production with SUS metabolized . This example illustrates the potential to admin isoforms is as follows: ister THC - glycosides orally , transit the THC - glycosides SrSus4 > SrSusl through the small intestine without absorption , transit to the Untagged > SrSus6 > SrSus2 > SrSus1 > 6x His large intestine where the sugars can be decoupled to release SrSus1 > SrSus3 THC locally , avoiding systemic absorption and delivery of the THC to the central nervous system where it can have Example 13 : Improved In Vitro Catalysis of unwanted psychoactivity . Cannabinoid -Glycosides [ 0288 ] As the formation of cannabinoid glycosides via Example 12 : Discovery of Novel Sucrose Synthase UGT enzyme requires the nucleotide sugar donor UDPG in Isoforms from Stevia rebaudiana stoichiometric amounts , it is advantageous to recycle or recapture the spent UDP following a glycosylation reaction . [ 0283 ] A number of research groups have utilized simple Utilizing the SUS4 isoform from Stevia rebaudiana , can UDP to UDPG recycling systems to decrease the amount of nabinoid glycosides were successfully produced using only UDPG needed for product formation (Hardin 2004, Bunga UMP as the input nucleotide . rang 2013 ) . These studies have characterized the primary [0289 ] A two step reaction took place, first to produce sucrose synthase isoforms found in leaf tissue, which pre UDP from UMP, and second to produce UDPG from the sumably carry out the synthesis of sucrose by reacting UDP in tandem with the UGT reaction . First, a 5L reaction fructose with UDPG , producing sucrose and spent UDP . containing 50 mM KPO , pH7. 2 , 200 mM UMP disodium [ 0284 ] As plants are known to contain numerous isoforms salt, 200 mM ATP disodium salt , 1M MgCl2 , 10 % UMPK of the sucrose synthase enzyme, identification of alternative recombinant enzyme in 50 % glycerol was prepared . The SUS enzymes from the Stevia rebaudiana plant with reaction was incubated at 28 C with stirring for > 24 hours . enhanced activity for the back reaction of UDP + sucro The 5L reaction 1 was filtered at 0 .45 microns to remove se - > UDPG + fructose was carried out. As steviol glycosides precipitate then applied to a 50L reaction containing 50 mM occur at a high level in Stevia leaves , it was postulated that KPO4 PH7. 2 , 50 mM MgCl2 , 300 mM Sucrose, 200 mg of a sucrose synthase from the leaves of Stevia would have CBD in 200 mlDMSO , 5L UGT76G1 in 50 % glycerol, 2 . 5L improved ability to catalyze the back reaction that recycles SrSUS4 in 50 % glycerol . The main 50L reaction was then UDP to UDPG . Six sucrose synthase isoforms were identi mixed and allowed to react. An additional 200 mg of CBD fied within the stevia transcriptome, all having similar in 200 ml DMSO was added after the reaction went to homology to the 6 isoforms found in Arabidopsis thaliana completion , and allowed to continue incubating at the same and named in conjunction with their homologues . These conditions . After the remaining CBD was consumed by the transcripts were cloned as described in materials and meth reaction , the mixture was filtered by tangential flow filtration ods with the corresponding sequence ID information listed with a ultrafiltration membrane at 5 kDa to remove enzymes herein . and particulate , and then concentrated using nanofiltration US 2018 /0264122 A1 Sep . 20 , 2018 49 membrane at 500 Da. The nanofiltration retentate containing vacuum beaker and lyophilized to dryness . The powdered the cannabosides was then applied to hydrated C18 flash cannabosides produced were then collected and stored at columns, washed with 10 - 30 % methanol, and eluted with - 20 C in sealed vials . Sucrose should be sterile filtered to 40 -65 % methanol. The eluate was then concentrated by avoid carmelization or sugar breakdown , as autoclaving rotary evaporation to remove all solvent, shell - frozen in a sucrose stock solutions greatly decreases reaction activity . TABLE 1 Cannabidiol- glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB # 1° 1 - 0 Position 2º 2 - 0 - 2° 3 - 0 3° 3 - 0 1° Position 2° 2 -0 - 2° 3 -0 VB101 R1 = H R2 = H VB102 R1 = B - D - glucose H R2 = H VB103 R1 = B - D - glucose B - D - glucose R2 = VB104 R1 = B - D - glucose H - glucose R2 ILLI= VB105 B - D - glucose B - D - glucose B - D - glucose R2 = VB106 R1 H R2 B - D - glucose VB107 R1 H R2 B - D - glucose B - D - glucose VB108 R1 = R2 = B - D - glucose H B - D - glucose VB109 R1 = R2 = B - D - glucose B - D - glucose B - D - glucose VB110 R1 = B - D - glucose R2 = B - D - glucose VB111 R1 = B - D - glucose B - D - glucose R2 = B - D - glucose VB112 R1 = se ?? B - D - glucoseose R2 = B - D - glucose VB113 R1 = B - D - glucose B - D - glucose B - D - glucose R2 = B - D - glucose VB114 R1 = R2 = B - D - glucose B - D - glucose VB115 R1 = B - D - glucose B - D - glucose R2 B - D - glucose B - D - glucose VB116 R1 = B - D - glucose H B - D - glucose R2 B - D - glucose B - D - glucose VB117 R1 = B - D - glucose B - D - glucose B - D -glucose R2 B - D - glucose B - D - glucose VB118 R11 = B - D - glucose R2 = B - D - glucose H B - D - glucose VB119 R1 = B - D - glucose ? B - D - glucose R2 = B - D - glucose H B - D - glucose VB120 R1 = B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB121 R1 = B - D - glucose B - D - glucose B - D - glucose R2 = B - D - glucose H B - D - glucose VB122 R1 = B - D - glucose R2 LLLLLLLLL|= B - D - glucose B -D - glucose B - D - glucose VB123 R1 = B - D - glucose B - D - glucose R2 = B - D - glucose B - D - glucose B - D - glucose VB124 R1 = B - D - glucose H B - D - glucose R2 = B - D -glucose B - D - glucose B - D - glucose VB125 R1 = B - D - glucose B - D - glucose B - D - glucose R2 = B - D - glucose B - D - glucose B - D - glucose VB126 R1 = a - D - glucose R2 ? VB127 R1 = H R2 = a - D - glucose VB128 R1 = a - D - glucose R2 = a - D - glucose VB129 R1 = B - D - glucose a - D - glucose R2 = VB130 R1 = H R2 = B - D - glucose a - D - glucose VB131 R1 = B - D - glucose a - D - glucose R2 = B -D -glucose a -D - glucose VB132 R1 B - D - glucose B - D - glucose B -D - glucose R2 = ? VB133 R1 = H R2 = B - D - glucose H . B - D - glucose VB134 R1 = B -D - glucose H B - D - glucose B - D - glucose R2 = B - D - glucose H B - D - glucose VB # 3° 3- 0 - Name 1° Enzyme 2° Enzyme VB101 Cannabidiol ( CBD ) VB102 CBD - 1 - 0 - glucopyranoside UGT76G1 VB103 CBD - 1- 0 -( 2 - 1) - diglucopyranoside UGT7661 Os03g0702000 VB104 CBD - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB105 CBD - 1 - 0 - ( 2 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB106 CBD - 2 - O - glucopyranoside UGT76G1 VB107 CBD - 2 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB108 CBD - 2 - 0 - ( 3 - 1 ) - diglucopyranoside UGT7661 VB109 CBD - 1 - 0 - ( 2 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB110 CBD - 1 , 2 - 0 - diglucopyranoside UGT76G1 VB111 CBD - 1 - 0 - ( 2 - 1 ) , 2 - O -triglucopyranoside UGT76G1 Os03g0702000 VB112 CBD - 1 - 0 - ( 3 - 1 ), 2 - O -triglucopyranoside UGT76G1 VB113 CBD - 1 - 0 - ( 2 - 1 , 3 - 1 ) , 2 - 0 - tetraglucopyranoside UGT76G1 Os03g0702000 VB114 CBD - 1 - 0 , 2 - 0 - ( 2 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB115 CBD - 1- 0 -( 2 - 1) , 2 -0 -( 2 - 1 )- tetraglucopyranoside UGT76G1 Os03g0702000 VB116 CBD - 1 - 0 - ( 3 - 1 ), 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB117 CBD - 1 - 0 - ( 2 - 1 , 3 - 1 ) , 2 - 0 - ( 2 - 1 ) -pentaglucopyranoside UGT76G1 Os03g0702000 VB118 CBD - 1 - 0 , 2 - 0 -( 3 - 1 ) -triglucopyranoside UGT76G1 VB119 CBD - 1 - 0 - ( 3 - 1 ), 2 - 0 - ( 3 - 1 )- tetraglucopyranoside UGT76G1 VB120 CBD - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB121 CBD - 1- 0 -( 2 - 1, 3 -1 ) , 2 -0 -( 3 - 1) - pentaglucopyranoside UGT76G1 Os03g0702000 VB122 CBD - 1 - 0 , 2 - 0 - ( 2- 1 , 3 - 1 ) -tetraglucopyranoside UGT76G1 Os03g0702000 VB123 CBD - 1 - 0 - ( 2 - 1 ) ,2 - 0 -( 2 - 1 ,3 - 1 )- pentaglucopyranoside UGT76G1 Os0380702000 US 2018 /0264122 A1 Sep . 20 , 2018 50

TABLE 1 -continued Cannabidiol -glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB124 CBD - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 2 - 1 , 3 - 1 ) -pentaglucopyranoside UGT76G1 Os03g0702000 VB125 CBD - 1 - 0 -( 2 - 1 ,3 - 1 ), 2 - 0 - (2 - 1, 3 - 1 )- hexaglucopyranoside UGT76G1 Os03g0702000 VB126 CBD - 1 - 0 - a - glucopyranoside CGTase VB127 CBD -2 - 0 - a - glucopyranoside CGTase VB128 CBD - 1 , 2 - 0 - a - glucopyranoside CGTase VB129 CBD - 1 - 0 - B - primed - a -diglucopyranoside UGT76G1 CGTase VB130 CBD - 2 - O -B -primed -a -diglucopyranoside UGT76G1 CGTase VB131 CBD - 1 , 2 - 0 - B - primed - a -diglucopyranoside UGT76G1 CGTase VB132 CBD - 1 - 0 - ( 3 - 1 , 3 - 1 ) -triglucopyranoside UGT7661 VB133 B - D - glucose CBD - 2 - 0 - ( 3- 1 , 3 - 1 )- triglucopyranoside UGT76G1 VB134 B -D - glucose CBD -1 , 2 - 0 -( 3 -1 , 3 -1 ) - hexaglucopyranoside UGT76G1

TABLE 2 Cannabidivarin - glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB # 1° 1 - 0 Position 2° 2 - 0 - 2° 3 - 0 3° 3 - 0 1° Position 2° 2 - 0 - 2° 3 - 0 VB201 R1 = H R2 = VB202 R1 = B - D - glucose R2 = VB203 R1 = B - D - glucose B - D - glucose R2 = VB204 R1 III B - D - glucose H B - D - glucose R2 = VB205 R1 = B - D - glucose B - D - glucose B - D - glucose R2 H VB206 R1 = R2 B - D - glucose VB207 R1 = B - D - glucose B - D - glucose VB208 R1 = B - D - glucose H B - D -glucose VB209 R1 = B - D - glucose B - D - glucose B - D - glucose VB210 R1 B - D - glucose AAAA B - D - glucose VB211 R1 ILL B - D - glucose B - D - glucose R2 B - D - glucose VB212 R1 = B - D - glucose H B - D - glucose R2 B - D - glucose VB213 R1 B - D - glucose B - D - glucose B - D - glucose R2 ILLLLLLLLLLLIII| B - D - glucose VB214 R1 = B - D - glucose R2 = B - D - glucose B - D - glucose VB215 R1 = B - D - glucose B - D - glucose R2 = B - D - glucose B - D - glucose VB216 R1 = B - D - glucose H B - D - glucose R2 B - D - glucose B - D - glucose VB217 R1 = B - D - glucose B - D - glucose B - D - glucose R2 B - D - glucose B - D - glucose VB218 R1 = B - D - glucose R2 B - D - glucose H B - D - glucose VB219 R1 = B - D - glucose B - D -glucose B - D - glucose H B - D - glucose VB220 R1 = B - D - glucose B - D - glucose II| B - D -glucose H B - D - glucose VB221 R1 = B - D - glucose B - D - glucose B - D - glucose B - D - glucose H B - D - glucose VB222 R1 B - D - glucose R2 IL| B - D - glucose B - D - glucose B - D - glucose VB223 R1 B - D - glucose B - D - glucose R2 B - D - glucose B - D - glucose B - D -glucose VB224 R1 B - D - glucose H B - D - glucose R2 II| B - D -glucose B - D - glucose B - D - glucose VB225 R1 B - D - glucose B - D - glucose B - D - glucose R2 B - D - glucose B - D - glucose B - D - glucose VB226 R1 a - D - glucose R2 II| ? VB227 R1 LLLLLLLL= H R2 = a - D - glucose VB228 R1 = a - D - glucose R2 = a - D - glucose VB229 R1 = B - D - glucosese a - D - glucose R2 = H VB230 R1 = R2 | B - D - glucose a - D - glucose VB231 R1 = B - D - glucose a - D - glucose R2 | B - D - glucose a - D - glucose VB232 R1 = B - D - glucose H B -D - glucose B -D -glucose R2 | VB233 R1 = R2 = B - D - glucose H B - D - glucose VB234 R1 = B - D - glucose H B -D - glucose B -D - glucose R2 = B -D -glucose H B - D - glucose VB # 3° 3 - 0 Name 1° Enzyme 2° Enzyme VB201 Cannabidiol (CBDV ) VB202 CBDV - 1 - 0 - glucopyranoside UGT7661 VB203 CBDV- 1 - 0 - ( 2 - 1 ) -diglucopyranoside UGT76G1 Os03g0702000 VB204 CBDV - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB205 CBDV - 1 - 0 - ( 2 - 1 ,3 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB206 CBDV- 2 -0 - glucopyranoside UGT76G1 VB207 CBDV - 2 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB208 CBDV - 2 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB209 CBDV- 1 - 0 -( 2 - 1 , 3 - 1) - triglucopyranoside UGT76G1 Os03g0702000 VB210 CBDV - 1 , 2 - 0 - diglucopyranoside UGT76G1 VB211 CBDV- 1 - 0 -( 2 - 1) , 2 - 0 - triglucopyranoside UGT76G1 Os03g0702000 VB212 CBDV - 1 - 0 - ( 3 - 1 ) , 2 - 0 - triglucopyranoside UGT76G1 VB213 CBDV- 1 - 0 -( 2 - 1 , 3- 1) , 2 - O -tetraglucopyranoside UGT76G1 Os03g0702000 VB214 CBDV - 1 - 0 ,2 - 0 -( 2 - 1 )- triglucopyranoside UGT76G1 Os03g0702000 VB215 CBDV - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 2 - 1 ) -tetraglucopyranoside UGT76G1 Os03g0702000 US 2018 /0264122 A1 Sep . 20 , 2018 51

TABLE 2 - continued Cannabidivarin -glycoside compositions by R - group R - group location is as depicted in FIG . 1B

VB216 CBDV - 1- 0 -( 3 -1 ), 2 -O - (2 - 1 )- tetraglucopyranoside UGT7661 Os03g0702000 VB217 CBDV- 1 - 0 - ( 2 - 1 , 3 - 1 ), 2 - 0 - ( 2 - 1 )- pentaglucopyranoside UGT7661 Os03g0702000 VB218 CBDV - 1 - 0 , 2- 0 -( 3 -1 )- triglucopyranoside UGT76G1 VB219 CBDV - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 3 - 1 ) -tetraglucopyranoside UGT76G1 VB220 CBDV- 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT7661 Os03g0702000 VB221 CBDV - 1 - 0 -( 2 -1 , 3 - 1 ) , 2 - 0 - ( 3 - 1 )- pentaglucopyranoside UGT76G1 Os03g0702000 VB222 CBDV - 1 - 0 ,2 -0 -( 2 - 1, 3 -1 ) -tetraglucopyranoside UGT76G1 Os03g0702000 VB223 CBDV - 1 - 0 - ( 2 - 1 ), 2 - 0 - ( 2 - 1 , 3 - 1 ) - pentaglucopyranoside UGT76G1 Os03g0702000 VB224 CBDV - 1 - 0 - (3 - 1 ), 2 - 0 - ( 2 - 1 , 3- 1 )- pentaglucopyranoside UGT7661 Os03g0702000 VB225 CBDV - 1 - 0 - ( 2 - 1 , 3 - 1 ) , 2 - 0 - ( 2 - 1 , 3 - 1 ) -hexaglucopyranoside UGT76G1 Os03g0702000 VB226 CBDV- 1 -0 - Q - glucopyranoside CGTase VB227 CBDV - 2 - 0 - a - glucopyranoside CGTase VB228 CBDV - 1 , 2 - 0 - a - glucopyranoside CGTase VB229 CBDV - 1 - 0 - B - primed - a - diglucopyranoside UGT76G1 CGTase VB230 CBDV - 2 - 0 -B -primed - a -diglucopyranoside UGT76G1 CGTase VB231 CBDV - 1, 2 -0 -B -primed -a -diglucopyranoside UGT76G1 CGTase VB232 CBDV - 1 - 0 - (3 - 1, 3 - 1) - triglucopyranoside UGT76G1 VB233 B - D - glucose CBDV - 2 - 0 -( 3 - 1 , 3 - 1 ) -triglucopyranoside UGT76G1 VB234 B - D - glucose CBDV - 1 , 2 - 0 -( 3 - 1, 3 - 1) - hexaglucopyranoside UGT76G1

TABLE 3 A9 - Tetrahydrocannabinol- glycoside compositions by R - group group location is as depicted in FIG . 1B VB # 1° 1 -0 Position 2° 2 -0 - 2° 3 -0 3° 3- 0 Name 1° Enzyme 2° Enzyme VB301 R1 A9 - Tetrahydrocannabinol VB302 R1 B - D - glucose ASTHC - 1 - 0 - glucopyranoside UGT76G1 VB303 R1 B - D - glucose B - D - glucose ASTHC - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1Os03g0702000 VB304 R1 B - D - glucose H B - D - glucose A9THC - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB305 R1 LLLLL B - D - glucose B - D - glucose B - D - glucose ASTHC - 1 - 0 - ( 2 - 1 , 3 - 1 ) UGT7661 Os03g0702000 triglucopyranoside VB306 R1 = a - D - glucose ASTHC - 1 - 0 - a - glucopyranoside CGTase VB307 R1 = a - D -glucose ASTHC - 1 - 0 - B -primed - a UGT76G1 CGTase diglucopyranoside VB308 R1 = B - D -glucose H B -D - glucose B - D - glucose A9THC- 1 - 0 - ( 3 - 1 , 3 - 1 ) UGT76G1 triglucopyranoside

TABLE 4 Cannabinol - glycoside compositions by R - group R - group location is as depicted in FIG . 1B 1° 1 - 0 VB # Position 2° 2 - 0 - 2° 3 - 0 3° 3 - 0 Name 1° Enzyme 2° Enzyme VB401 R1 = ? Cannabinol VB402 R1 = B - D - glucose CBN - 1 - O - glucopyranoside UGT7661 VB403 R1 = B - D - glucose B - D - glucose CBN - 1 - O -( 2 - 1 ) -diglucopyranoside UGT76G1 Os03g0702000 VB404 R1 = B - D - glucose H B - D - glucose CBN - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB405 R1 = B - D - glucose B - D - glucose B - D - glucose CBN - 1 - 0 - ( 2 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 2000 VB406 R1 = a - D - glucose CBN - 1 - O - a - glucopyranoside CGTase VB407 R1 = B - D - glucose a - D - glucose CBN - 1 - 0 - B - primed - a - diglucopyranoside UGT76G1 CGTase VB408 R1 = B - D - glucoseH B - D - glucose B - D - glucose CBN - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 US 2018 /0264122 A1 Sep . 20 , 2018

TABLE 5 Anandamide ( AEA ) glycoside Compositions by R - group R - group location is as depicted in FIG . 1B 1° 1 - 0 VB # Position 2° 2 - 0 - 2° 3 - 0 3° 3 - 0 Name 1° Enzyme 2º Enzyme VB501 R1 = H . Anandamide (AEA ) VB502 R1 = B - D - glucose AEA - 1 - 0 - glucopyranoside UGT76G1 VB503 R1 = B - D - glucose H B - D - glucose AEA - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB504 R1 = B - D -glucose B - D - glucose AEA - 1 - 0 -( 2 -1 ) -diglucopyranoside UGT76G1 Os03g0702000 VB505 R1 = B - D - glucoseH B - D - glucose B - D - glucose AEA - 1 - 0 - ( 3 - 1 , 3 - 1 ) -triglucopyranoside UGT76G1 VB506 R1 = B - D -glucose B - D - glucose B - D -glucose AEA - 1 - 0 - ( 3 - 1 , 2 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB507 R1 = a - D - glucose AEA - 1 - 0 - a - glucopyranoside CGTase VB508 R1 = B - D - glucose - D - glucose AEA - 1 - 0 - B -primed - a -diglucopyranoside UGT76G1 CGTase

TABLE 6 2 - Arachidonoylglycerol ( 2 - AG ) - glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB # 1° 1 -0 Position 2° 2 -0 - 2° 3- 0 3° 3- 0 2° Position 2° 2- 0 - 2° 3- O VB601 R1 = H R2 = H VB602 R1 = B - D - glucose R2 = H VB603 R1 = H R2 B - D - glucose VB604 R1 = B - D - glucose B - D - glucose R2 VB605 R1 = B - D - glucose H B - D - glucose VB606 R1 = B - D - glucose B - D - glucose VB607 R1 = IILLLLLLLLLL B - D - glucose H B - D - glucose VB608 R1 = B - D - glucose B - D - glucose VB609 R1 ILL B - D - glucose R2 B - D - glucose H B - D - glucose VB610 R1 = B - D - glucose ? B -D - glucose R2 B - D - glucose VB611 R1 = B - D - glucose R2 B - D - glucose B - D - glucose VB612 R1 = B - D - glucose . B - D - glucose B - D - glucose H VB613 R1 = ? R2 = B - D - glucose H B - D - glucose VB614 R1 = B - D - glucose B - D - glucose R2 B - D - glucose

VB615 R1 = B - D - glucose ? B -D - glucose R2 |L B - D - glucose H B - D - glucose VB616 R1 = B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB617 R1 = B - D - glucose B - D - glucose = B - D - glucose B - D - glucose VB618 R1 = B - D - glucose B -D -glucose R2 = B - D - glucose B - D - glucose VB619 R1 = a - D - glucose ? VB620 R1 = B - D -glucose a - D - glucose R2 H VB621 R1 H R2 = a - D - glucose VB622 R1 = H R2 = B - D - glucose a - D - glucose VB623 R1 = a - D - glucose R2 LLLLLL= a - D - glucose VB # 3° 3- 0 Name 1° Enzyme 2° Enzyme VB601 2 - Arachidonoylglycerol ( 2 - AG ) VB602 2 - AG - 1 - O - glucopyranoside UGT76G1 VB603 2 - AG - 2 - 0 - glucopyranoside UGT76G1 VB604 2 - AG - 1 -0 - (3 - 1 )- diglucopyranoside UGT76G1 VB605 2 - AG - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB606 2 - AG - 2 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB607 2 - AG - 2 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB608 2 - AG - 1 - 0 , 2 - 0 - diglucopyranoside UGT76G1 VB609 2 - AG - 1 - 0 , 2 - 0 - ( 3 - 1 ) -triglucopyranoside UGT76G1 VB610 2 - AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - triglucopyranoside UGT76G1 VB611 2 - AG - 1 - 0 , 2 - 0 - ( 2 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB612 2 - AG - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 VB613 B - D - glucose 2 - AG - 2 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT7661 VB614 2 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 -triglucopyranoside UGT76G1 Os03g0702000 VB615 2 - AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 VB616 2 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 Os0390702000 VB617 2 -AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB618 2 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB619 2 - AG - 1 - 0 - a - glucopyranoside CGTase VB620 2 - AG - 1 - 0 - B - primed - a -diglucopyranoside UGT76G1 CGTase VB621 2 - AG - 2 - 0 - a - glucopyranoside CGTase VB622 2 - AG - 2 - 0 - B - primed - a - diglucopyranoside UGT76G1 CGTase VB623 2 - AG - 1 , 2 - 0 - a - diglucopyranoside CGTase US 2018 /0264122 A1 Sep . 20 , 2018 53

TABLE 7 1 - Arachidonoylglycerol ( 1 -TABLES AG ) - glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB # 1° 1- 0 Position 2° 2 - 0 - 2° 3- 0 - 3º 3- 0 2° Position 2° 2 - 0 - 2° 3- 0 VB701 R1 = H . ? VB702 R1 = B - D - glucose H VB703 R1 = H B - D - glucose VB704 R1 = B - D - glucose B - D - glucose VB705 R1 = B - D - glucose H B - D - glucose VB706 R1 A B - D - glucose B - D - glucose VB707 R1 = B - D - glucose H B - D - glucose VB708 R1 = B - D - glucose R2NNNNNN B - D - glucose VB709 R1 ILLLLL= B - D - glucose R2 B - D - glucose H B - D - glucose VB710 R1 = B - D - glucose ? B - D - glucose R2 B - D - glucose VB711 R1 |11 R2 LLLLLLLLLLL B - D - glucose B - D - glucose B - D - glucose VB712 R1 LI B - D - glucose B - D - glucose R2 B - D - glucose VB713 R1 = B - D - glucose H B -D - glucose B -D -glucose VB714 R1 = ? R2 = B - D - glucose H B - D - glucose VB715 R1 = B - D - glucose B -D - glucose R2 B - D - glucose H B - D - glucose VB716 R1 = B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB717 R1 = B - D - glucose H B - D - glucose R2 B - D - glucose B - D - glucose VB718 R1 = B - D - glucose B - D - glucose B - D - glucose B - D - glucose VB719 R1 = a - D - glucose 2 ILLLLLLLLL VB720 R1 = B - D - glucose a - D - glucose R2 VB721 R1 = H R2 = a - D - glucose VB722 R1 = H R2 = B - D - glucose a - D - glucose VB723 R1 = a - D - glucose R2 = a - D - glucose VB # 3° 3 - 0 Name 1° Enzyme 2º Enzyme VB701 1 - Arachidonoylglycerol ( 1 - AG ) VB702 1 - AG - 1 - O - glucopyranoside UGT76G1 VB703 1 - AG - 2 - 0 - glucopyranoside UGT76G1 VB704 1 - AG - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 VB705 1 - AG - 1 - 0 -( 3 - 1 )- diglucopyranoside UGT76G1 Os03g0702000 VB706 1 - AG - 2 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 VB707 1 - AG - 2 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB708 1 - AG - 1 - 0 , 2 - 0 - diglucopyranoside UGT76G1 VB709 1 - AG - 1 - 0 , 2 - 0 - ( 3 - 1 ) -triglucopyranoside UGT76G1 VB710 1 - AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - triglucopyranoside UGT76G1 VB711 1 - AG - 1 - 0 , 20 - ( 2 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB712 1 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 - triglucopyranoside UGT76G1 Os03g0702000 VB713 1 - AG - 1 - 0 - ( 3 - 1 , 3 - 1 ) -triglucopyranoside UGT76G1 VB714 B - D - glucose 1 - AG - 2 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 VB715 1 - AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 VB716 1 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB717 1 - AG - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB718 1 - AG - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB719 1 - AG - 1 - 0 - a - glucopyranoside CGTase VB720 1- AG - 1 - 0 - B -primed - a -diglucopyranoside UGT76G1 CGTase VB721 1 - AG - 2 - 0 - a - glucopyranoside CGTase VB722 1 - AG - 2 - 0 - B -primed - a -diglucopyranoside UGT76G1 CGTase VB723 1 - AG - 1 , 2 - 0 - a -diglucopyranoside CGTase

TABLE 8 Docosahexaenoyl ethanoloamide (DHEA ) glycoside compositions by R - group R - group location is as depicted in FIG . 1B 1° 1 - 0 VB # Position 2° 2 - 0 2° 3 - 0 3° 3 - 0 Name 1° Enzyme 2° Enzyme VB801 R1 = H Docosahexaenoyl ethanoloamide (DHEA ) VB802 R1 = B - D - glucose DHEA - 1 - 0 - glucopyranoside UGT76G1 VB803 R1 = B - D - glucose H B - D - glucose DHEA - 1 - 0 - ( 3 - 1 ) -diglucopyranoside UGT7661 VB804 R1 = B - D - glucose B - D - glucose DHEA - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT7661 Os03g0702000 VB805 R1 = B - D - glucose H B - D - glucose B - D - glucose DHEA - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 VB806 R1 = a - D - glucose B - D - glucose B - D - glucose DHEA - 1 - 0 - ( 3 - 1 , 2 - 1 ) - triglucopyranoside UGT7661 Os03g0702000 VB807 R1 IILLLL| a - D - glucose DHEA - 1 - 0 - a - glucopyranoside CGTase VB808 R1 = B - D - glucose a - D - glucose DHEA - 1 - 0 - B - primed - a UGT76G1 CGTase diglucopyranoside US 2018 /0264122 A1 Sep . 20 , 2018 54

TABLE 9 Capsiacin glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB # 1° 1- 0 Position 2° 2 -0 - 2° 3- 0 - 3º 3- 0 Name 1° Enzyme 2° Enzyme VB901 R1 = H . Capsaicin VB902 R1 = B - D - glucose Capsaicin - 1 - 0 - glucopyranoside UGT76G1 VB903 R1 = B - D - glucose H B - D - glucose Capsaicin - 1 - 0 - ( 3 - 1 ) -diglucopyranoside UGT76G1 VB904 R1 = B - D - glucose B - D - glucose Capsaicin - 1 - 0 - ( 2 - 1 ) -diglucopyranoside UGT7661 Os03g0702000 VB905 R1 = B - D - glucosese B - D - glucose B - D -glucose Capsaicin - 1 - 0 - ( 3 - 1 , 3 - 1 ) UGT76G1 triglucopyranoside VB906 R1 = B - D - glucose B - D - glucose B - D -glucose Capsaicin - 1 - 0 - ( 2 - 1 , 3 - 1 ) UGT7661 Os03g0702000 triglucopyranoside VB907 R1 = a - D - glucose Capsiacin - 1 - 0 - a - glucopyranoside CGTase VB908 R1 = B - D - glucose a - D - glucose Capsiacin - 1 - 0 - B -primed - a UGT76G1 CGTase diglucopyranoside

TABLE 10 Vanillin glycoside compositions by R - group R - group location is as depicted in FIG . 1B 1° 1 - 0 VB # Position 2° 2 - 0 2° 3 - 0 3° 3 - 0 Name 1° Enzyme 2º Enzyme VB1001 R1 = H Vanillin VB1002 R1 = B - D -glucose Vanillin - 1 - 0 - glucopyranoside UGT7661 VB1003 R1 = B - D - glucose H B - D - glucose Vanillin - 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB1004 R1 = B - D - glucose B - D - glucose Vanillin - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB1005 R1 = B - D - glucose B - D - glucose B - D - glucose Vanillin - 1 - 0 - ( 2 - 1 , 3 - 1 ) - triglucopyranoside UGT7661 Os03g0702000 VB1006 R1 = B - D - glucose H B - D - glucose B - D - glucose Vanillin - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 VB1007 R1 = a - D - glucose Vanillin - 1 - O - a - glucopyranoside CGTase VB1008 R1 = B - D - glucose a - D - glucose Vanillin - 1 - 0 - B -primed - a UGT76G1 CGTase diglucopyranoside

TABLE 11 Curcumin glycoside compositions by R - group R -group location is as depicted in FIG . 1B VB # 1° 1 -0 Position 2° 2 - 0 - 2° 3 -0 3° 3 - 0 2° Position 2° 2- 0 - 2° 3 -0 VB1101 R1 = H R2 = H VB1102 R1 = B - D - glucose R2 = VB1103 R1 = ? R2 | B - D - glucose VB1104 R1 = B - D - glucoseOse H B - D - glucose R2 | H VB1105 R1 = B - D - glucose B - D - glucose R2 = VB1106 R1 = R2 = B - D - glucose H B - D - glucose VB1107 R1 = ? R2 B - D - glucose B - D - glucose VB1108 R1 = B - D - glucose R2 B - D - glucose VB1109 R1 = B - D - glucose R2 B - D - glucose H B - D - glucose VB1110 R1 B - D - glucose ? B - D - glucose B - D - glucose H VB1111 R1 = B - D - glucose ? B - D - glucose B - D - glucose VB1112 R1 = B - D - glucose B - D - glucose B - D - glucose VB1113 R1 B - D - glucoseose B - D - glucose B - D - glucose R2 H VB1114 R1 = R2 B - D - glucose B - D - glucose B - D - glucose VB1115 R1 LLLLL= H R2 B - D - glucose H B - D - glucose VB1116 R1 = B - D - glucose H B - D - glucose B - D - glucose ? VB1117 R1 = se B - D - glucose R2 B - D - glucose H B - D - glucose VB1118 R1 = B - D - glucose B - D - glucose R2 = B - D - glucose H B - D - glucose VB1119 R1 = B - D - glucose H? B - D - glucose R2 |= B - D - glucose B - D - glucose VB1120 R1 = B - D - glucose B - D -glucose R2 = B - D - glucose B - D - glucose |LLLLLLLLLLLL VB1121 R1 = B - D - glucose B - D - glucose B - D - glucose B - D - glucose VB1122 R1 = B - D - glucose B - D - glucose B - D - glucose R2 | B - D - glucose VB1123 R1 B - D - glucose R2 B - D - glucose H B - D - glucose VB1124 R1 = B - D - glucose R2 B - D - glucose B - D - glucose B - D -glucose VB1125 R1 = B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB1126 R1 LLLL B - D - glucose H B - D - glucose R2 B - D - glucose B - D - glucose VB1127 R1 B - D - glucose B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB1128 R1 = B - D - glucose B - D - glucose H B - D - glucose R2 B - D - glucose H B - D - glucose VB1129 R1 = B - D - glucoseH B - D - glucose B - D - glucose R2 B - D - glucose H B - D - glucose VB1130 R1 = B - D - glucose B - D - glucose H B - D - glucose R2 ILLLLL= B - D - glucose H B - D - glucose US 2018 /0264122 A1 Sep . 20 , 2018 55

TABLE 11 - continued Curcumin glycoside compositions by R - group R - group location is as depicted in FIG . 1B VB1131 R1 = B - D - glucoseH B - D - glucose B - D - glucose R2 = B - D -glucose B - D - glucose H VB1132 R1 = Q - D - glucose R2 = H VB1133 R1 = B - D - glucose - D - glucose R2 = VB1134 R1 = H = A - D - glucose VB1135 R1 = R2 = B - D - glucose a - D - glucose VB1136 R1 = a - D - glucose R2 = a - D - glucose VB # 3° 3 - 0 Name 1° Enzyme 2° Enzyme VB1101 Curcumin VB1102 Curcumin - 1 - 0 - glucopyranoside UGT7661 VB1103 Curcumin - 2 - 0 - glucopyranoside UGT76G1 VB1104 Curcumin- 1 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB1105 Curcumin - 1 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB1106 Curcumin - 2 - 0 - ( 3 - 1 ) - diglucopyranoside UGT76G1 VB1107 Curcumin - 2 - 0 - ( 2 - 1 ) - diglucopyranoside UGT76G1 Os03g0702000 VB1108 Curcumin - 1 - 0 , 2 - 0 - diglucopyranoside UGT76G1 VB1109 Curcumin - 1 - 0 , 2 - 0 - ( 3 - 1 ) - triglucopyranoside UGT76G1 VB1110 Curcumin - 1 - 0 - ( 3 - 1 ) , 2 - 0 - triglucopyranoside UGT76G1 VB1111 Curcumin - 1 - 0 , 2 - 0 - ( 2 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB1112 Curcumin - 1 - 0 - ( 2 - 1 ) , 2 - O - triglucopyranoside UGT76G1 Os03g0702000 VB1113 Curcumin- 1 - 0 - ( 2 - 1 , 3 - 1 ) -triglucopyranoside UGT76G1 Os03g0702000 VB1114 Curcumin - 2 - 0 - ( 2 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 Os03g0702000 VB1115 B - D - glucose Curcumin - 2 - 0 - ( 3 - 1 , 3 - 1 ) -triglucopyranoside UGT76G1 VB1116 Curcumin - 1 - 0 - ( 3 - 1 , 3 - 1 ) - triglucopyranoside UGT76G1 VB1117 Curcumin - 1 - 0 -( 3 - 1) , 2 - 0 - ( 3 - 1 )- tetraglucopyranoside UGT76G1 VB1118 Curcumin - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 3 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB1119 Curcumin - 1 - 0 - (3 - 1 ), 2 - 0 -( 2 - 1 )- tetraglucopyranoside UGT76G1 Os03g0702000 VB1120 Curcumin - 1 - 0 - ( 2 - 1 ) , 2 - 0 - ( 2 - 1 ) - tetraglucopyranoside UGT76G1 Os03g0702000 VB1121 Curcumin - 1 - 0 - ( 3 - 1 , 3 - 1 ) , 2 - 0 - tetraglucopyranoside UGT76G1 VB1122 Curcumin - 1 - 0 - (2 - 1 ,3 - 1 ), 2 - 0 -tetraglucopyranoside UGT76G1 Os03g0702000 VB1123 B - D - glucose Curcumin - 1 - 0 , 20 - ( 3 - 1 , 3 - 1 ) - tetraglucopyranoside UGT76G1 VB1124 Curcumin - 1 - 0 , 2 - 0 - ( 2 - 1 , 3 - 1 ) -tetraglucopyranoside UGT76G1 Os03g0702000 VB1125 B - D - glucose Curcumin - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 3 - 1 , 3 - 1 ) -pentaglucopyranoside UGT76G1 VB1126 B - D - glucose Curcumin - 1 - 0 - ( 3 - 1 ) , 2 - 0 - ( 2 - 1 , 3 - 1 ) -pentaglucopyranoside UGT76G1 Os03g0702000 VB1127 Curcumin - 1 - 0 - ( 3 - 1 , 3 - 1 ) , 2 - 0 - ( 3 - 1 ) -pentaglucopyranoside UGT7661 VB1128 Curcumin - 1 - 0 - ( 2 - 1 , 3 - 1 ) , 2 - 0 - ( 3 - 1 ) -pentaglucopyranoside UGT76G1 Os03g0702000 VB1129 B - D - glucose Curcumin - 1 - 0 - ( 3 - 1 , 3 - 1 ) , 2 - 0 - ( 3 - 1 , 3 - 1 ) - hexaglucopyranoside UGT76G1 VB1130 B - D - glucose Curcumin - 1 - 0 - ( 2 - 1 , 3 - 1 ) , 2 - 0 - ( 3 - 1 , 3 - 1 ) - hexaglucopyranoside UGT76G1 Os03g0702000 VB1131 B - D - glucose Curcumin - 1 - 0 - ( 3 - 1 , 3 - 1 ) , 2 - 0 - ( 2 - 1 , 3 - 1 ) -hexaglucopyranoside UGT76G1 Os03g0702000 VB1132 Curcumin - 1 - 0 - a - glucopyranoside CGTase VB1133 Curcumin - 1 - 0 - B - primed - a - diglucopyranoside UGT76G1 CGTase VB1134 Curcumin - 2 - 0 - a - glucopyranoside CGTase VB1135 Curcumin - 2 - 0 - B - primed - a - diglucopyranoside UGT76G1 CGTase VB1136 Curcumin - 1 , 2 - 0 - Q - glucopyranoside CGTase

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SEQUENCE LISTING

< 160 > NUMBER OF SEQ ID NOS : 34 < 210 > SEQ ID NO 1 1 > LENGTH : 458 < 212 > TYPE : PRT < 213 > ORGANISM : Stevia rebaudiana < 400 > SEQUENCE : 1 Met Glu Asn Lys Thr Glu Thr Thr Val Arg Arg Arg Arg Arg Ile Ile 10 15 US 2018 / 0264122 Al Sep. 20 , 2018 57

- continued | Leu Phe &Pro Val Pro Phe Gln Gly His Ile Asn Pro Ile Leu Gln Leu a 25 TEAAla Asn EVal Leu Tyr Ser Lys Gly Phe Ser Ile Thr Ile Phe His Thr 35 40 1 45 Asn Phe Asn Lys Pro Lys Thr Ser Asn Tyr Pro His Phe Thr Phe Arg Phe Ile Leu Asp Asn Asp Pro Gin Asp Glu Arg Ile Ser Asn Leu Pro 65 &He 80 1 Thr His Gly Pro Leu Ala Gly Met Arg Ile Pro Ile Ile Asn Glu His

Gly Ala Asp Glu Leu Arq Arq Glu Leu Glu Leu Leu Met Leu Ala Ser 105

Glu Glu Asp Glu Glu Val Ser cys Leu Ile ?Thr Asp Ala Leu Trp Tyr | 115 120 125 Phe Ala Gin Ser Val Ala Asp Ser Leu Asn Leu Arg Arg Leu Val Leu

Met Thr Ser Ser Leu Phe Asn Phe His Ala His Val Ser Leu Pro Gin 145 160 Phe Asp Glu Leu Gly Tyr Leu Asp Pro Asp Asp Lys Thr Arg Leu Glu Glu Gin Ala Ser Gly Phe Pro Met Leu Lys Val Lys Asp Ile Lys Ser 185 Ala Tyr Ser Asn Trp Gin Ile Leu Lys Glu Ile Leu Gly Lys Met Ile 195 200 205 Lys Gin Thr Lys Ala Ser Ser Gly Val Ile Trp Asn Ser Phe Lys Glu

Leu Glu Glu Ser Glu Leu Glu Thr Val Ile Arq Glu Ile Pro Ala Pro 225 240 Ser Phe Leu Ile Pro Leu Pro Lys His Leu Thr Ala Ser Ser S r Ser

Leu Leu Asp His Asp Arg Thr Val Phe Gin Trp Leu Asp Gin Gin Pro 265 Pro Ser Ser Val Leu Tyr Val Ser Phe Gly Ser Thr Ser Glu Val Asp 275 280 285 Glu Lys Asp Phe Leu Glu Ile Ala Arg Gly Leu Val Asp Ser Lys Gin

Ser Phe Leu Trp Val Val Arg Pro Gly Phe Val Lys Gly Ser Thr Trp 305 320 Val Glu Pro Leu Pro Asp Gly Phe Leu Gly Glu Arg Gly Arg mmmmIle Val Lys Trp Val Pro Gin Gin Glu Val Leu Ala His Gly Ala Ile Gly Ala 345

Phe Trp ?Thr His Ser Gly Trp Asn Ser Thr Leu Glu Ser Val Cys Glu 355 360 365

Gly Val &Pro Met Ile Phe Ser Asp Phe Gly Leu Asp Gin Pro Leu Asn

Ala Arg Tyr Met Ser Asp Val Leu Lys Val Gly Val Tyr Leu Glu Asn 385 400 Gly Trp Glu Arg Gly Glu Ile Ala Asn Ala Ile Arg Arg Val Met Val 415 Asp Glu Glu Gly Glu Tyr Ile Arg Gin Asn Ala Arg m?Val mmmLeu Lys Gin US 2018 /0264122 A1 Sep . 20 , 2018 58

- continued 420 425 430 Lys Ala Asp Val Ser Leu Met Lys Gly Gly Ser Ser Tyr Glu Ser Leu 435 440 445 Glu Ser Leu Val Ser Tyr Ile Ser Ser Leu 450 455

< 210 > SEQ ID NO 2 < 211 > LENGTH : 1377 < 212 > TYPE : DNA < 213 > ORGANISM : Stevia rebaudiana < 400 > SEQUENCE : 2 atggaaaata aaacggagac caccgttcgc cggcgccgga gaataatatt attcccggta 60 ccatttcaag gocacattaa cccaattctt cagctagcca atgtgttgta ctctaaagga 120 ttcagtatca ccatctttca caccaacttc aacaaacccaaaacatctaa ttaccctcac 180 ttcactttca gattcatcct cgacaacgac ccacaagacg aacgcatttc caatctaccg 240 actcatggtc cgctcgctgg tatgoggatt ccgattatca acgaacacgg agctgacgaa 300 ttacgacgcg aactggaact gttgatgtta gcttctgaag aagatgaaga ggtatcgtgt 360 ttaatcacgg atgctctttg gtacttcgcg caatctgttg ctgacagtct taacctccga 420 cggcttgttt tgatgacaag cagettgttt aattttcatg cacatgtttc acttcctcag 480 tttgatgagc ttggttacct cgatcctgat gacaaaaccc gtttggaaga acaagcgagt 540 gggtttccta tgctaaaagt gaaagacatc aagtctgcgt attcgaactg gcaaatactc 600 aaagagatat tagggaagat gataaaacaa acaagagcat cttcaggagt catctggaac 660 tcatttaagg aactcgaaga gtctgagctc gaaactgtta tccgtgagat cccggctcca 720 agtttcttga taccactccc caagcatttg acagcctctt ccagcagctt actagaccac 780 gatcgaaccg tttttcaatg gttagaccaa caaccgccaa gttcggtact gtatgttagt 840 tttggtagta ctagtgaagt ggatgagaaa gatttcttgg aaatagctcg tgggttggtt 900 gatagcaagc agtcgttttt atgggtggtt cgacctgggt ttgtcaaggg ttcgacgtgg 960 gtcgaaccgt tgccagatgg gttcttgggt gaaagaggac gtattgtgaa atgggttcca 1020 cagcaagaag tgctagotca tggagcaata ggcgcattct ggactcatag cggatggaac 1080 tctacgttgg aaagcgtttg tgaaggtgtt cctatgattt tctcggattt tgggctcgat 1140 caaccgttga atgctagata catgagtgat gttttgaagg taggggtgta tttggaaaat 1200 gggtgggaaa gaggagagat agcaaatgca ataagaagag ttatggtgga tgaagaagga 1260 gaatacatta gacagaatge aagagttttg aaacaaaagg cagatgtttc tttgatgaag 1320 ggtggttcgt cttacgaatc attagagtct ctagtttctt acatttcatc gttgtaa 1377

< 210 > SEQ ID NO 3 < 211 > LENGTH : 467 ?< 212 > TYPE : PRT ?< 213 > ORGANISM : Artificial Sequence ?< 220 > FEATURE : < 223M > OTHER INFORMATION : UGT76G1 with a 6x Histidine tag at the N - terminus < 400 > SEQUENCE : 3 Met His His His His His His Gly Ser Gly Glu Asn Lys Thr Glu Thr 10 15 US 2018 / 0264122 Al Sep. 20 , 2018 59 .

- continued Thr Val Arg Arg Arg Arg Arg Ile Ile Leu Phe Pro Val Pro Phe Gln 20 25 30 Gly His Ile Asn Pro Ile Leu Gin Leu Ala Asn Val Leu Tyr Ser Lys 40 m 45 Gly Phe Ser Ile Thr °Ile Phe His Thr Asn Phe Asn Lys Pro Lys Thr

8? Ser Asn Tyr Pro His Phe Thr Phe Ara Phe Ile Leu Asp Asn Asp Pro 65 70 75

Gin Asp Glu Arg Ile Ser Asn Leu Pro Thr His Gly &Pro Leu Ala Gly

Met Arq Ile Pro Ile Ile Asn Glu His Gly Ala Asp Glu Leu Arq Arq 100 105 110 Glu Leu Glu Leu Leu Met Leu Ala Ser Glu Glu Asp Glu Glu Val Ser 115 120 125

Cys Leu Ile Thr Asp Ala Leu Trp Tyr Phe Ala Gln Ser Val Ala Asp

Ser Leu Asn Leu Arg Arg Leu Val Leu Met Thr Ser Ser Leu Phe Asn 145 150 155 Phe His Ala His Val Ser Leu Pro Gln Phe Asp Glu Leu Gly Tyr Leu

Asp Pro Asp Asp Lys Thr Arg Leu Glu Glu Gin Ala Ser Gly Phe Pro 180 185 190 Met Leu Lys Val Lys Asp Ile Lys Ser Ala Tyr Ser Asn Trp Gin Ile 195 200 205 Leu Lys Glu Ile Leu Gly Lys Met Ile Lys Gin Thr Lys Ala Ser Ser

Gly Val Ile Trp Asn Ser Phe Lys Glu Leu Glu Glu Ser Glu Leu Glu 225 230 235 Thr Val Ile Arg Glu Ile Pro Ala Pro Ser Phe Leu Ile Pro Leu Pro

Lys His Leu Thr Ala Ser Ser Ser Ser Leu Leu Asp His Asp Arg Thr 260 265 270 Val Phe Gin Trp Leu Asp Gin Gin Pro Pro Ser Ser Val Leu Tyr Val 275 280 285 Ser Phe Gly Ser Thr Ser Glu Val Asp Glu Lys Asp Phe Leu Glu Ile Ala Arg Gly Leu Val Asp Ser Lys Gin Ser Phe Leu Trp Val Val Arg ?mm305 310 315 Pro Gly Phe Val Lys Gly Ser Thr Trp Val Glu Pro Leu Pro Asp Gly Phe Leu Gly Glu Arg Gly Arg Ile Val Lys Trp Val Pro Gin Gin Glu 340 mmm 345 350 Val Leu Ala His Gly Ala Ile Gly Ala Phe Trp Thr His Ser Gly Trp 355 360 365 Asn Ser Thr Leu Glu Ser Val Cys Glu Gly Val Pro Met Ile Phe Ser 375 mmmmm Asp Phe Gly Leu Asp Gin Pro Leu Asn Ala Arg Tyr Met Ser Asp Val 385 mmm 390 395 mmmmm Leu Lys Val Gly Val Tyr Leu Glu Asn Gly Trp Glu Arg Gly Glu Ile mmmmm405 415 Ala Asn mmmmAla mmmmmmIle Arg Arg Val Met mmmmmVal mmmAsp mmmmmmmGlu Glu Gly Glu Tyr Ile US 2018 /0264122 A1 Sep . 20 , 2018

- continued 420 425 430 Arg Gln Asn Ala Arg Val Leu Lys Gln Lys Ala Asp Val Ser Leu Met 435 440 445 Lys Gly Gly Ser Ser Tyr Glu Ser Leu Glu Ser Leu Val Ser Tyr Ile 450 455 460 Ser Ser Leu 465

< 210 > SEQ ID NO 4 < 211 > LENGTH : 1404 < 212 > TYPE : DNA < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Sequence encoding SEQ ID NO : 3 codon optimized for expression in Pichia pastoris < 400 > SEQUENCE : 4 atgcaccacc atcaccacca tggttctggt gaaaacaaaa ctgaaactac tgttagaaga 60 agaagaagaa tcattttgtt tccagtacca tttcaaggcc atatcaatcc aattcttcaa 120 ttggccaatg ttttgtactc caaaggattc tccatcacca tttttcacac caatttcaac 180 aaaccaaaga cttccaacta tcctcacttc actttcagat ttattttgga taatgatcct 240 caagatgaaa gaatttccaa tcttccgact catggtcctt tggctggtat gagaattcca 300 atcatcaatg aacatggtgc tgatgaatta agaagagaat tggaactttt gatgttggct 360 totgaagaag atgaagaagt ttcatgttta atcactgatg ctttatggta ttttgctcaa 420 tctgttgctg attctttgaa tttgcgacgg ttggttttga tgacttcttc tttgttcaac 480 tttcatgctc atgtttcttt acctcagttt gatgaacttg gatatttgga tccagatgac 540 aaaactagat tggaagaaca agctagtggg tttcctatgt tgaaagtcaa agatatcaaa 600 tctgcttact ccaactggca aattctcaaa gaaattttgg gaaaaatgat caaacaaaca 660 aaagcttctt ctggagtcat ttggaactca ttcaaagaat tggaagaatc tgaattggaa 720 actgttatta gagaaattcc tgctccaagt tttttgattc ctttgccaaa acatttgact 780 gottcttctt cttctttatt ggatcacgat agaactgttt ttcaatggtt agatcaacaa 840 cctccatctt ctgttttgta tgttagtttt ggatctactt ctgaagttga tgaaaaagat 900 tttttggaaa ttgctagagg tttggttgat tccaaacaaa gttttttatg ggttgttaga 960 ccaggatttg tcaaaggatc tacttgggtc gaacctttgc cagatggatt tttgggagaa 1020 agaggaagaa ttgtcaaatg ggttccacag caagaagttt tggctcatgg tgctattggt 1080 gctttttgga ctcattctgg atggaactct actttggaat ctgtttgtga aggtgttcca 1140 atgatttttt ctgattttgg tttggatcaa ccattgaatg ctagatacat gtctgatgtt 1200 ttgaaagttg gtgtttattt ggaaaatggg tgggaaagag gtgaaattgc caatgctatt 1260 agaagagtca tggttgatga agaaggagaa tacattagac aaaatgctag agttttgaaa 1320 caaaaagctg atgtttcttt gatgaagggt ggatcttctt atgaatcttt ggaatctttg 1380 qtttcttaca tttcttctct ttaa 1404

< 210 > SEQ ID NO 5 ?< 211 > LENGTH : 468 ?< 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220NEP > FEATURE : US 2018 / 0264122 Al Sep. 20 , 2018

- continued < 223 > OTHER INFORMATION : UGT76G1 with a 6x Histidine - Glutamine tag at the N - terminus < 400 > SEQUENCE : 5 Met His Gin His Gln His Gin Ser Gly Ser Met Glu Asn Lys Thr Glu 15

Thr Thr Val Ara Arg Arg Arg Arg Ile Ile Leu Phe Pro Val &Pro Phe & g 30 Gin Gly His Ile Asn Pro Ile Leu Gin Leu Ala Asn Val Leu Tyr Ser 40 ? Lys Gly Phe Ser Ile Thr Ile Phe His Thr Asn Phe Asn Lys &Pro Lys

Thr Ser Asn Tyr Pro His Phe Thr Phe Arq Phe gIle Leu Asp Asn Asp ne&R 70 | Pro Gin Asp Glu Arg Ile Ser Asn Leu &Pro Thr His Gly Pro Leu Ala °2 95

Gly Met Ara Ile Pro Ile Ile Asn Glu His Gly Ala Asp Glu Leu Arq 110 Arg Glu Leu Glu Leu Leu Met Leu Ala Ser Glu Glu Asp Glu Glu Val 120 Ser Cys Leu Ile Thr Asp Ala Leu Trp Tyr Phe Ala Gin Ser Val Ala

Asp Ser Leu Asn Leu Arg Arg Leu Val Leu Met Thr Ser Ser Leu Phe 150

Asn Phe His Ala His Val Ser Leu Pro Gln Phe Asp Glu Leu Gly Tyr 175 Leu Asp Pro Asp Asp Lys Thr Arg Leu Glu Glu Gin Ala Ser Gly Phe 190 Pro Met Leu Lys Val Lys Asp Ile Lys Ser Ala Tyr Ser Asn Trp Gin 200 Ile Leu Lys Glu Ile Leu Gly Lys Met Ile Lys Gin Thr Lys Ala Ser

Ser Gly Val Ile Trp Asn Ser Phe Lys Glu Leu Glu Glu Ser Glu Leu 230 mmm Glu Thr Val Ile Arg Glu Ile Pro Ala Pro Ser Phe Leu Ile &Pro Leu mam 255 Pro Lys His Leu Thr Ala Ser Ser Ser Ser Leu Leu Asp His DAsp Arq 270 Thr Val Phe Gin Trp Leu Asp Gin Gin Pro Pro Ser Ser Val Leu Tyr 280 Val Ser Phe Gly Ser Thr Ser Glu Val Asp Glu Lys Asp Phe Leu Glu

Ile Ala Arg Gly Leu Val Asp Ser Lys Gin Ser Phe Leu Trp Val Val 310 Arg Pro Gly Phe Val Lys Gly Ser Thr Trp Val Glu Pro Leu Pro Asp 335 Gly Phe Leu Gly Glu Arg Gly Arg Ile Val Lys Trp Val Pro Gin Gin 350 Glu Val Leu Ala His Gly Ala Ile Gly Ala Phe Trp Thr His Ser Gly 360 Trp Asn Ser Thr Leu Glu Ser Val Cys Glu Gly Val Pro Met Ile Phe 370 375 mmm mmmg US 2018 /0264122 A1 Sep . 20 , 2018 62

- continued

Ser Asp Phe Gly Leu Asp Gin Pro Leu Asn Ala Arg Tyr Met PenSer Asp 390 395 400 Val Leu Lys Val Gly Val Tyr Leu Glu Asn Gly Trp Glu Arg Gly Glu

g Ile Ala Asn Ala Ile Arg Arg Val Met Val Asp Glu Glu Gly Glu Tyr 425 Ile Arg Gin Asn Ala Arg Val Leu Lys Gin Lys Ala Asp Val Ser Leu 435 440 Met Lys Gly Gly Ser Ser Tyr Glu Ser Leu Glu Ser Leu Val Ser Tyr sota 455 460 Ile Ser Ser Leu 465

< 210 > SEQ ID NO 6 < 211 > LENGTH : 1407 < 212 > TYPE : DNA < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Sequence encoding SEQ ID NO : 5 codon optimized for expression in Pichia pastoris < 400 > SEQUENCE : 6 atgcatcaac atcaacacca atctggatct atggagaaca agaccgagac tacagttaga 60 agaagaagaa gaataatcct gtttccagta ccattccaag gacacatcaa cccaatcttg 120 cagttagcaa atgtacttta ttctaaaggc tttagtatta cgatttttca cactaatttt 180 aataagccaa aaacatccaa ttaccctcac ttcacattca gatttatctt ggataacgat 240 cctcaagatg aacgtatctc caacctgcca acacatggac cattggccgg tatgcgtatt 300 cctataatca acgagcatgg tgctgatgag cttagacgtg aactggaact gttgatgctg 360 gcatcggagg aagatgaaga ggttagttgc ttgataacgg atgccctctg gtatttcgca 420 caatcagtcg ctgactcctt gaaccttagg agattggtat tgatgactag ttcgttgttc 480 aacttccatg cccatgtttc tttgcctcaa tttgatgagc tgggttattt ggatcctgac 540 gataagactc gtttagaaga acaggcgtca ggcttcccca tgttaaaggt taaagatatt 600 aagtccgcct attctaactg gcaaattctc aaagagattc tagggaaaat gattaaacaa 660 accaaggcct cttcaggagt aatctggaac agtttcaaag aactagaaga atccgagttg 720 gaaactgtta ttcgtgaaat ccctgctcca tctttcctta tcccattacc aaagcacctc 780 actgcctcct ctagttctct tctggaccat gatagaacag tctttcagtg gctcgatcag 840 caacctccat cttctgtctt gtacgttagt tttggttcca cctcggaagt agatgaaaaa 900 gactttctgg aaattgctcg aggactagtt gactccaagc aatcctttct gtgggttgtt 960 agacctggat tcgtaaaagg atccacctgg gtagaacccc toccagatgg atttttgggc 1020 gaaaggggaa gaattgttaa atgggtgcct caacaagaag ttttagctca tggggccatt 1080 ggagcttttt ggactcatag tggatggaat tctaccttag aatctgtttg tgaaggagtt 1140 ccaatgattt tttctgattt tggattggat cagcctctta atgccagata tatgtccgat 1200 gtcctcaagg tcggagtgta cctggaaaat ggttgggaga gaggtgagat tgcaaatgct 1260 atacgtagag tcatggttga tgaagagggc gagtatatta gacaaaacgc tagagtgcta 1320 aagcagaagg ccgatgtttc ccttatgaag gggggaagtt catatgagag tttggaatcc 1380 US 2018 / 0264122 Al Sep. 20 , 2018 62

- continued ctagtgtcct acatttcttc gctataa 1407

< 210 > SEQ ID No 7 < 21111 > LENGTH : 466 < 21212 > TYPE : PRT V< 21313 > ORGANISM : Artificial Sequence ( 2) 220 0 > FEATURE :

V 2 < 2233 > OTHER INFORMATION : UGT76G1 with a 6x Histidine tag at the C - terminus < 400 > SEQUENCE : 7 | Met Glu Asn Lys Thr Glu Thr Thr Val Arg Arg RArg Arg Arg Ile Ile 15

Leu Phe Pro Val Pro Phe Gin Gly His Ile Asn &Pro Ile Leu Gln Leu

Ala Asn Val Leu Tyr Ser Lys Gly Phe Ser Ile ?Thr Ile Phe His Thr 35 40

Asn Phe Asn Lys Pro Lys Thr Ser Asn Tyr Pro His Phe ?Thr Phe Arq

Phe Ile Leu Asp Asn Asp Pro Gin Asp Glu Arg Ile Ser Asn Leu Pro 65 80 Lie& ?Thr His Gly Pro Leu Ala Gly Met Arg Ile Pro °Ile Ile Asn Glu His 95 Gly Ala Asp Glu Leu Arg Arg Glu Leu Glu Leu Leu Met Leu Ala Ser

Glu Glu Asp Glu Glu Val Ser Cys Leu Ile Thr Asp Ala Leu Trp Tyr 115 120 Phe Ala Gln Ser Val Ala Asp Ser Leu Asn Leu Ara Arq Leu Val Leu

Met Thr Ser Ser Leu Phe Asn Phe His Ala His Val Ser Leu Pro Gin 145 160 Phe Asp Glu Leu Gly Tyr Leu Asp Pro Asp Asp Lys Thr Arg Leu Glu 175 Glu Gin Ala Ser Gly Phe Pro Met Leu Lys Val Lys Asp Ile Lys Ser

Ala Tyr Ser Asn Trp Gln Ile Leu Lys Glu Ile Leu Gly Lys Met Ile 195 200 Lys Gin Thr Arg Ala Ser Ser Gly Val Ile Trp Asn Ser Phe Lys Glu

Leu Glu Glu Ser Glu Leu Glu Thr Val Ile Arg Glu Ile &Pro Ala Pro 225 240 Ser Phe Leu Ile Pro Leu Pro Lys His Leu Thr Ala Ser Ser Ser Ser 255

Leu Leu Asp His Asp Arg Thr Val Phe Gin Trp Leu Asp SGin Gin Pro

Pro Ser Ser Val Leu Tyr Val Ser Phe Gly Ser Thr Ser Glu Val Asp 275 280 Glu Lys Asp Phe Leu Glu Ile Ala Arg Gly Leu Val Asp Ser Lys Gin

Ser Phe Leu Trp Val Val Arg Pro Gly Phe Val Lys Gly Ser Thr Trp 305 320 Val Glu Pro Leu Pro Asp Gly Phe Leu Gly Glu Arg Gly Arg Ile Val 0 335 US 2018 / 0264122 Al Sep. 20 , 2018 64

- continued | Lys Trp Val Pro Gin Gin Glu Val ?Leu Ala His Gly Ala Ile Gly Ala 340 345 350 Phe Trp Thr His Ser Gly Trp Asn Ser Thr Leu Glu Ser Val Cys Glu 355 360

2Gly Val &Pro Met Ile Phe Ser Asp Phe Gly Leu Asp Gin Pro Leu Asn EERP370 . 380 Ala Arq 2Tyr Met Ser Asp Val Leu Lys Val Gly Val Tyr Leu Glu Asn 385 400

2Gly Trp 3Glu Arg Gly EDGlu Ile Ala Asn Ala Ile Arg Arg Val Met Val Asp Glu Glu Gly Glu Tyr Ile Arg Gin Asn Ala Arg Val Leu Lys ???|Gin 420 EELDE 425 mm 430 Lys Ala Asp Val Ser Leu gp?Met Lys Gly Gly Ser Ser Tyr Glu Ser Leu 435 440

3Glu Ser Leu Val Ser Tyr Ile Ser Ser Leu Gly Ser His His His His 450 Ile ser ser leu Gly 460ser Hisa His Eas His His 465

< 210 > SEQ ID No 8 < 2111 > LENGTH : 1401 < 2121 > TYPE : DNA < 2131 > ORGANISM : Artificial Sequence < 2202 > FEATURE : < 2232 > OTHER INFORMATION : Sequence encoding SEQ ID NO : 7 codon optimized for expression in Escherichia coli < 400 > SEQUENCE : 8 atggaaaata aaaccgaaac caccgtccgt cgccgtcgtc gtatcattct gttcccggtc 60 ccgttccaag gtcacatcaa cccgattctg cagctggcca acgtgctgta tagcaaaggt 120 ttctctatca ccatcttcca tacgaacttc aacaaaccga aaacctctaa ctacccgcac 180 tttacgttcc gttttattct ggataacgac ccgcaggatg aacgcatcag taatctgccg 240 acccatggtc cgctggcggg tatgcgtatt ccgattatca acgaacacgg cgcagatgaa 300 - ctgcgtcgcg aactggaact gctgatgctg gcctctgaag aagatgaaga agttagttgc 360 ctgatcaccg acgcactgtg gtattttgcc cagagtgttg cagattccct gaacctgcgt | 420 cgcctggtcc tgatgacgag ctctctgttc aattttcatg cccacgtttc cctgccgcag 480 ttcgatgaac tgggttatct ggacccggat gacaaaaccc gcctggaaga acaagcttca 540 ggctttccga tgctgaaagt caaagatatt aaaagtgcgt actccaactg gcagattctg 600 aaagaaatcc tgggtaaaat gatcaaacaa acccgtgcaa gttccggcgt catctggaat 660 tccttcaaag aactggaaga atcagaactg gaaacggtga ttcgcgaaat cccggctccg 720 tcttttctga ttccgctgcc gaaacatctg accgcgtcat cgagctctct gctggatcac 780 gaccgtacgg tgtttcagtg gctggatcag caaccgccga gttccgtgct gtacgttage 840 ttcggtagca cctctgaagt ggatgaaaaa gactttctgg aaatcgctcg tggcctggtt 900 gattcaaaac aatcgttcct gtgggtggtt cgcccgggtt ttgtgaaagg cagcacgtgg 960 gttgaaccgc tgccggatgg cttcctgggt gaacgtggtc gcattgtcaa atgggtgccg 1020 cagcaagaag tgctggcaca tggtgctatc ggcgcgtttt ggacccactc aggttggaac 1080 tcgacgctgg aaagcgtttg tgaaggtgtc ccgatgattt tctcggattt tggcctggac 1140 US 2018 / 0264122 Al Sep. 20 , 2018 65

- continued cagccgctga atgcacgtta tatgagcgat gttctgaaag tcggtgtgta cctggaaaac 1200 ggttgggaac gcggcgaaat tgcgaatgcc atccgtcgcg ttatggtcga tgaagaaggc 1260 gaatatatcc gtcagaatgc tcgcgtcctg aaacaaaaag cggacgttag tctgatgaaa 1320 ggcggttcat cgtacgaatc cctggaatca ctggtctcct acatttcttc tctgggctcg | 1380 catcatcatc atcatcatta a 1401

< 210 > SEQ ID NO 9 < 211 > LENGTH : 472 < 212 > TYPE : PRT < 213 > ORGANISM : Oryza sativa < 400 > SEOUENCE : 9 Met His Gin His Gin His Gin Ser Gly Ser Met Asp Ser Gly Tyr Ser | . 15

Ser Ser Tyr Ala Ala Ala Ala Gly Met His Val Val Ile Cys Pro Trp 25 | 30 23 Leu Ala Phe Gly His Leu Leu Pro Cys Leu Asp Leu Ala Gln Arg Leu 135 40 Ala Ser Arg Gly His Arq Val Ser Phe Val Ser Thr Pro Arq Asn Ile

Ser Arq Leu Pro Pro Val Arq Pro Ala Leu Ala Pro Leu Val Ala Phe 70 Val Ala Leu Pro Leu Pro Arg Val Glu Gly Leu Pro Asp Gly Ala Glu 85 95 Ser Thr Asn Asp Val Pro His Asp Arq Pro Asp Met Val Glu Leu His 105 110 Arg Arg Ala Phe Asp Gly Leu Ala Ala Pro Phe Ser Glu Phe Leu Gly 115 120 R Thr Ala Cys Ala Asp Trp Val Ile Val Asp Val Phe His His Trp Ala

E Ala Ala Ala Ala Leu Glu His Lys Val Pro Cys Ala Met Met Leu Leu 150 Gly Ser Ala His Met Ile Ala Ser Ile Ala Asp Arg Arg Leu Glu Arg 165 175 Ala Glu Thr Glu Ser Pro Ala Ala Ala Gly Gin Gly Arg Pro Ala Ala 185 190 Ala Pro Thr Phe Glu Val Ala Arg Met Lys Leu Ile Arg Thr Lys Gly 195 200 Ser Ser Gly Met Ser Leu Ala Glu Arg Phe Ser Leu Thr Leu Ser Arg Ser Ser Leu Val Val Gly Arg Ser Cys Val Glu Phe Glu Pro Glu Thr 230 Val Pro Leu Leu Ser Thr Leu Arg Gly Lys Pro Ile Thr Phe Leu Gly 245 255

Leu Met &Pro Pro Leu His Glu Gly Arg Arg Glu Asp Gly Glu Asp Ala 265 270 Thr Val Arg Trp Leu Asp Ala Gin Pro Ala Lys Ser Val Val Tyr Val E275 280 Ala Leu Gly Ser Glu Val Pro Leu Gly Val Glu Lys Val His Glu Leu 295 smmmmmAla mmmmLeu Gly Leu Glu Leu Ala Gly Thr Arg Phe Leu Trp Ala Leu Arg US 2018 / 0264122 Al Sep. 20 , 2018

- continued | 310 315 320 Lys &Pro ?Thr 0Gly Val Ser Asp Ala Asp Leu Leu Pro Ala Gly Phe Glu 330

Glu Arg Thr Arg Gly Arg Gly Val Val Ala Thr HArg Trp Val &Pro Gin 340 345 350

Met Ser Ile Leu Ala His Ala Ala Val Gly Ala Phe Leu ?Thr His Cys 355 360

Gly Trp Asn Ser Thr Ile Glu Gly Leu Met Phe 2Gly His Pro Leu Ile 375 E? Met Leu Pro Ile Phe Gly Asp Gin Gly Pro Asn Ala Arg Leu Ile Glu 390 395

Ala Lys ?Asn Ala Gly Leu Gin Val Ala Arg Asn Asp Gly Asp Gly Ser 410 Phe Asp Arg Glu Gly Val Ala Ala Ala Ile Arg Ala Val Ala Val Glu 420 425 430 Glu Glu Ser Ser Lys Val Phe Gin Ala Lys Ala Lys Lys Leu Gin Glu 435 mmmm440 Ile Val Ala Asp Met Ala Cys His Glu Arg Tyr Ile Asp Gly Phe Ile 450 455 ? Gin Gin Leu Arg Ser mmmTyr RE Lys Asp mmmm HEE 465 470

< 210 > SEQ ID NO 10 < 211 > LENGTH : 1419 < 212 > TYPE : DNA < 213 > ORGANISM : Oryza sativa < 400 > SEQUENCE : 10 atgcatcagc accaacatca gagcggttct atggactccg gctactcctc ctcctacgcc 60 gccgccgccg ggatgcacgt cgtgatctgc ccgtggctcg ccttcggcca cctgctcccg 120 tgcctcgacc tcgcccagcg cctcgcgtcg cggggccacc gcgtgtcgtt cgtctccacg 180 ccgcggaaca tatcccgcct cccgccggtg cgccccgcgc tcgcgccgct cgtcgccttc 240 gtggcgctgc cgctcccgcg cgtcgagggg ctccccgacg gcgccgagtc caccaacgac 300 gtcccccacg acaggccgga catggtcgag ctccaccgga gggccttcga cgggctcgcc 360 gcgcccttct cggagttctt gggcaccgcg tgcgccgact gggtcatcgt cgacgtcttc 420 caccactggg ccgcagccgc cgctctcgag cacaaggtgc catgtgcaat gatgttgttg 480 ggctctgcac atatgatcgc ttccatagca gacagacggc tcgagcgcgc ggagacagag 540 tcgcctgcgg ctgccgggca gggacgccca gcggcggcgc caacgttcga ggtggcgagg 6000 atgaagttga tacgaaccaa aggctcatcg ggaatgtccc tcgccgagcg cttctccttg 660 acgctctcgaggagcagcct cgtcgtcggg cggagctgcg tggagttcga gccggagacc 720 gtcccgctcc tgtcgacgct ccgcggtaag cctattacct tccttggcct tatgccgccg 780 ttgcatgaag gccgccgcga ggacggcgag gatgccaccg tccgctggct cgacgcgcag 840 ccggccaagt ccgtcgtgta cgtcgcgcta ggcagcgagg tgccactggg agtggagaag 900 gtccacgagc tcgcgctcgg gctggagctc gccgggacgc gcttcctctg ggctcttagg 960 aagcccactg gcgtctccga cgccgacctc ctccccgccg gottcgagga gcgcacgcgc 1020 ggccgcggcg tcgtggcgac gagatgggtt cctcagatga gcatactggc gcacgccgcc 1080 US 2018 / 0264122 Al Sep. 20 , 2018 67

- continued gtgggcgcgt tcctgaccca ctgcggctgg aactcgacca tcgaggggct catgtteggc 1140 cacccgctta tcatgctgcc gatcttcggc gaccagggac cgaacgcgcg gctaatcgag 1200 gcgaagaacg coggattgca ggtggcaaga aacgacggcg atggatcgtt cgaccgagaa 1260 ggcgtcgcgg cggcgattcg tgcagtcgcg gtggaggaag aaagcagcaa agtgtttcaa 1320 gccaaagcca agaagctgca ggagatcgtc gcggacatgg cctgccatga gaggtacatc 1380 gacggattca ttcagcaatt gagatcttac aaggattga 1419

< 210 > SEQ ID NO 11 < 400 > SEQUENCE : 11 000

< 210 > SEQ ID NO 12 < 400 > SEOUENCE : 12 000

< 210 > SEQ ID NO 13 < 211 > LENGTH : 4601 < 212 > TYPE : PRT < 213 > ORGANISM : Stevia rebaudi ana < 400 > SEQUENCE : 13 Met Ala Glu Gin Gin Lys Ile Lys Lys Ser Pro His Val Leu Leu Ile

&Pro Phe &Pro Leu Gln Gly His Ile Asn &Pro Phe Ile Gln Phe Gly Lys o 25 30 Arg Leu Ile Ser Lys Gly Val Lys Thr Thr Leu Val Thr Thr Ile His 40 1

?Thr Leu Asn Ser Thr Leu Asn His Ser Asn Thr Thr Thr ?Thr Ser Ile 55 Glu Ile Gin Ala Ile Ser Asp Gly cys Asp Glu Gly Gly Phe Met Ser

Ala Gly Glu Ser Tyr Leu Glu Thr Phe Lys Gin Val Gly Ser Lys Ser

Leu Ala Asp Leu Ile Lys Lys Leu Gin Ser Glu Gly Thr Thr Ile Asp 105 110 Ala Ile Ile Tyr Asp Ser Met Thr Glu Trp Val Leu Asp Val Ala Ile 120

Glu Phe Gly Ile Asp 3Gly Gly Ser Phe Phe Thr Gin Ala Cys Val Val 135

Asn Ser Leu Tyr Tyr His Val His Lys Gly Leu Ile Ser Leu &Pro Leu

Gly Glu Thr Val Ser Val Pro Gly Phe Pro Val Leu Gin Arg Trp Glu

Thr Pro Leu Ile Leu Gin Asn His Glu Gin Ile Gin Ser Pro Trp Ser 185 190 Gin Met Leu Phe Gly Gin Phe Ala Asn Ile Asp Gin Ala Arg Trp Val 200 Phe Thr Asn Ser Phe Tyr Lys Leu Glu Glu Glu mamaVal Ile Glu Trp Thr ? 215 ?