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Recombinant Production of Steviol Glycosides

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Recombinant Production of Steviol Glycosides (19) TZZ¥ZZZ_T (11) EP 3 009 508 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 20.04.2016 Bulletin 2016/16 C12N 9/00 (2006.01) C12N 9/10 (2006.01) C12N 9/90 (2006.01) C12N 15/81 (2006.01) (2006.01) (2006.01) (21) Application number: 15193074.0 C12N 15/82 C12P 19/44 (22) Date of filing: 08.08.2012 (84) Designated Contracting States: • NAESBY, Michael AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 4051 Basel (CH) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • OSTERGAARD, Tange Thomas PL PT RO RS SE SI SK SM TR 4057 Basel (CH) • HANSEN, Jorgen (30) Priority: 08.08.2011 US 201161521084 P 2000 Frederiksberg (DK) 08.08.2011 US 201161521203 P • DALGAARD MIKKELSEN, Michael 08.08.2011 US 201161521051 P 2500 Valby (DK) 15.08.2011 US 201161523487 P • HALKJAER, Hansen Esben 07.12.2011 US 201161567929 P 1972 Frederiksberg (DK) 27.02.2012 US 201261603639 P •SIMON,Ernesto 1118 Copenhagen (DK) (62) Document number(s) of the earlier application(s) in • DE ANDRADE PEREIRA TAVARES, Sabina accordance with Art. 76 EPC: 4053 Basel (CH) 12750513.9 / 2 742 142 (74) Representative: Smaggasgale, Gillian Helen (71) Applicant: Evolva SA WP Thompson 4153 Reinach (CH) 138 Fetter Lane London EC4A 1BT (GB) (72) Inventors: • HOUGHTON-LARSEN, Jens Remarks: 2920 Charlottenlund (DK) This applicationwas filed on 4.11.2015 as a divisional • HICKS, Paula M. application to the application mentioned under INID Bend, OR 97702 (US) code 62. (54) RECOMBINANT PRODUCTION OF STEVIOL GLYCOSIDES (57) Recombinant microorganisms, plants, and plant produce steviol glycosides, e.g., Rebaudioside A and/or cells are disclosed that have been engineered to express Rebaudioside D, which can be used as natural sweeten- recombinant genes encoding UDP-glycosyltransferases ers in food products and dietary supplements. (UGTs). Such microorganisms, plants, or plant cells can EP 3 009 508 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 009 508 A1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims priority to U.S. Application Serial No. 61/521,084, filed August 8, 2011; U.S. Application Serial No. 61/521,203, filed August 8, 2011; U.S. Application Serial No. 61/521,051, filed August 8, 2011; U.S. Application Serial No. 61/523,487, filed August 15, 2011; U.S. Application Serial No. 61/567,929, filed December 7, 2011; and U.S. Application Serial No. 61/603,639, filed February 27, 2012, all of which are incorporated by reference herein in their entirety. 10 TECHNICAL FIELD [0002] This disclosure relates to the recombinant production of steviol glycosides. In particular, this disclosure relates to theproduction of steviol glycosides such as rebaudioside Dby recombinant hosts such as recombinant microorganisms, 15 plants, or plant cells. This disclosure also provides compositions containing steviol glycosides. The disclosure also relates to tools and methods for producing terpenoids by modulating the biosynthesis of terpenoid precursors of the squalene pathway. BACKGROUND 20 [0003] Sweeteners are well known as ingredients used most commonly in the food, beverage, or confectionary indus- tries. The sweetener can either be incorporated into a final food product during production or for stand-alone use, when appropriately diluted, as a tabletop sweetener or an at-home replacement for sugars in baking. Sweeteners include naturalsweeteners suchas sucrose, high fructose cornsyrup, molasses, maple syrup,and honey and artificial sweeteners 25 such as aspartame, saccharine and sucralose. Stevia extract is a natural sweetener that can be isolated and extracted from a perennial shrub, Stevia rebaudiana. Stevia is commonly grown in South America and Asia for commercial pro- duction of stevia extract. Stevia extract, purified to various degrees, is used commercially as a high intensity sweetener in foods and in blends or alone as a tabletop sweetener. [0004] Extracts of the Stevia plant contain rebaudiosides and other steviol glycosides that contribute to the sweet 30 flavor, although the amount of each glycoside often varies among different production batches. Existing commercial products are predominantly rebaudioside A with lesser amounts of other glycosides such as rebaudioside C, D, and F. Stevia extracts may also contain contaminants such as plant-derived compounds that contribute to off-flavors. These off-flavors can be more or less problematic depending on the food system or application of choice. Potential contaminants include pigments, lipids, proteins, phenolics, saccharides, spathulenol and other sesquiterpenes, labdane diterpenes, 35 monoterpenes,decanoic acid,8,11,14-eicosatrienoic acid, 2-methyloctadecane, pentacosane,octacosane, tetracosane, octadecanol, stigmasterol, β-sitosterol, α- and β-amyrin, lupeol, β-amryin acetate, pentacyclic triterpenes, centauredin, quercitin, epi-alpha-cadinol, carophyllenes and derivatives, beta-pinene, beta-sitosterol, and gibberellin. SUMMARY 40 [0005] Provided herein is a recombinant host, such as a microorganism, plant, or plant cell, comprising one or more biosynthesis genes whose expression results in production of steviol glycosides such as rebaudioside A, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, or dulcoside A. In particular, EUGT11, a uridine 5’-diphospho (UDP) glycosyl transferase described herein, can be used alone or in combination with one or more other UDP glycosyl trans- 45 ferases such as UGT74G1, UGT76G1, UGT85C2, and UGT91D2e, to allow the production and accumulation of rebau- dioside D in recombinant hosts or using in vitro systems. As described herein, EUGT11 has a strong 1,2-19-O-glucose glycosylation activity, which is an important step for rebaudioside D production. [0006] Typically, stevioside and rebaudioside A are the primary compounds in commercially-produced stevia extracts. Stevioside is reported to have a more bitter and less sweet taste than rebaudioside A. The composition of stevia extract 50 can vary from lot to lot depending on the soil and climate in which the plants are grown. Depending upon the sourced plant, the climate conditions, and the extraction process, the amount of rebaudioside A in commercial preparations is reported to vary from 20 to 97% of the total steviol glycoside content. Other steviol glycosides are present in varying amounts in stevia extracts. For example, Rebaudioside B is typically present at less than 1-2%, whereas Rebaudioside C can be present at levels as high as 7-15%. Rebaudioside D is typically present in levels of 2% or less, and Rebaudioside 55 F is typically present in compositions at 3.5% or less of the total steviol glycosides. The amount of the minor steviol glycosides affects the flavor profile of a Stevia extract. In addition, Rebaudioside D and other higher glycosylated steviol glycosides are thought to be higher quality sweeteners than Rebaudioside A. As such, the recombinant hosts and methods described herein are particularly useful for producing steviol glycoside compositions having an increased 2 EP 3 009 508 A1 amount of Rebaudioside D for use, for example, as a non-caloric sweetener with functional and sensory properties superior to those of many high-potency sweeteners. [0007] In one aspect, this document features a recombinant host that includes a recombinant gene encoding a polypep- tide having at least 80% identity to the amino acid sequence set forth in SEQ ID NO:152. 5 [0008] This document also features a recombinant host that includes a recombinant gene encoding a polypeptide having the ability to transfer a second sugar moiety to the C-2’ of a 19-O-glucose of rubusoside. This document also features a recombinant host that includes a recombinant gene encoding a polypeptide having the ability to transfer a second sugar moiety to the C-2’ of a 19-O-glucose of stevioside. [0009] In another aspect, this document features a recombinant host that includes a recombinant gene encoding a 10 polypeptide having the ability to transfer a second sugar moiety to the C-2’ of the 19-O-glucose of rubusoside and to the C-2’ of the 13-O-glucose of rubusoside. [0010] This document also features a recombinant host that includes a recombinant gene encoding a polypeptide having theability to transfera second sugar moiety to the C-2’ of a 19-O-glucose ofrebaudioside A to produce rebaudioside D, wherein the catalysis rate of the polypeptide is at least 20 times faster (e.g., 25 or 30 times faster) than a 91D2e 15 polypeptide having the amino acid sequence set forth in SEQ ID NO: 5 when the reactions are performed under corre- sponding conditions. [0011] In any of the recombinant hosts described herein, the polypeptide can have at least 85% sequence identity (e.g., 90%, 95%, 98%, or 99% sequence identity) to the amino acid sequence set forth in SEQ ID NO:152. The polypeptide can have the amino acid sequence set forth in SEQ ID NO: 152. 20 [0012] Any of the hosts described herein further can include a recombinant gene encoding a UGT85C polypeptide having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:3. The UGT85C polypeptide can include one or more amino acid substitutions at residues 9, 10, 13, 15, 21, 27, 60, 65, 71, 87, 91, 220, 243, 270, 289, 298, 334, 336, 350, 368, 389, 394, 397, 418, 420, 440, 441, 444, and 471 of SEQ ID NO:3. [0013] Any of the hosts described herein further can include a recombinant gene encoding a UGT76G polypeptide 25 having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:7. The UGT76G polypeptide can have one or more amino acid substitutions at residues 29, 74, 87, 91, 116, 123, 125, 126, 130, 145, 192, 193, 194, 196, 198, 199, 200, 203, 204, 205, 206, 207, 208, 266, 273, 274, 284, 285, 291, 330, 331, and 346 of SEQ ID NO:7.
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