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WO 2015/028324 A2 5 March 2015 (05.03.2015) P O P C T

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WO 2015/028324 A2 5 March 2015 (05.03.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/028324 A2 5 March 2015 (05.03.2015) P O P C T (51) International Patent Classification: Copenhagen (DK). MEYER, Jean Philippe; C/O Evolva C12N 9/10 (2006.01) SA, Duggingerstrasse 23, CH-4153 Reinach (CH). VAZQUEZ, Carlos Casado; C/O Evolva SA, Dugginger (21) International Application Number: strasse 23, CH-41 53 Reinach (CH). PCT/EP2014/067520 (74) Agent: SMAGGASGALE, Gillian, Helen; 55 Drury (22) International Filing Date: Lane, London WC2B 5SQ (GB). 15 August 2014 (15.08.2014) (81) Designated States (unless otherwise indicated, for every English (25) Filing Language: kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/872,452 30 August 2013 (30.08.2013) US HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 61/873,348 3 September 2013 (03.09.2013) US KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/917,928 18 December 201 3 (18. 12.2013) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/923,486 3 January 2014 (03.01 .2014) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicant: EVOLVA SA [CH/CH]; Duggingerstrasse 23, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, CH-4153 Reinach (CH). TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors: BAERENDS, Richard Jan Steven; C/O Evolva SA, Duggingerstrasse 23, CH-4153 Reinach (CH). (84) Designated States (unless otherwise indicated, for every SIMON, Ernesto; 2nd Floor, Svaertegade 7, DK-1 118 kind of regional protection available): ARIPO (BW, GH, [Continued on nextpage] (54) Title: A METHOD FOR PRODUCING MODIFIED RESVERATROL (57) Abstract: Methods for producing glycosylated and Figure 1 methylated resveratrol in a genetically engineered cell, by bioconversion,and in vitro are disclosed herein. OH PAL L-phenylalanine Trans-cinnamic acid C4H < © o o w o 2015/028324 A2 1II II II 11 I Illlll 111 III III Hill lllll II 11 11 llll llll 11llll GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Published: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, — without international search report and to be republished TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, upon receipt of that report (Rule 48.2(g)) EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, — with sequence listing part of description (Rule 5.2(a)) SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, — with information concerning incorporation by reference GW, KM, ML, MR, NE, SN, TD, TG). of missing parts and/or elements (Rule 20.6) A METHOD FOR PRODUCING MODIFIED RESVERATROL BACKGROUND OF THE INVENTION Field of the Invention [0001] The invention disclosed herein relates generally to the fields of genetic engineering. Particularly, the invention disclosed herein provides purified preparations of glycosylated or methylated resveratrol and methods for producing and recovering glycosylated or methylated resveratrol from a genetically modified cell. More particularly, the invention disclosed herein provides glycosylated resveratrol preparations having improved solubility for use in foodstuffs and other commercial products and methods for using glycosylated resveratrol of the invention in producing said products. Description of Related Art [0002] Resveratrol (3,5,4'-trihydroxy-stilbene) is a phytophenol belonging to the group of stilbene phytoalexins, which are low-molecular-mass secondary metabolites that constitute the active defense mechanism in plants in response to fungal and other infections or other stress- related events (see, e.g., U.S. 2008/0286844). In addition to its antifungal properties, resveratrol has been recognized for its cardioprotective and cancer chemopreventive activities; it acts as a phytoestrogen, an inhibitor of platelet aggregation (Kopp et al., 1998, European J Endocrinol. 138: 619-620; Gehm et al., 1997, Proc Natl Acad Sci USA 94: 14138-14143; Lobo et al., 1995, Am. J. Obstet. Gynecol. 173: 982-989; Gao & Ming, 2010, Mini Rev Med Chem 10(6):550-67), and an antioxidant (Tang et al., 1997, Science 275: 218-220; Huang, 1997, Food Sci. 24: 713-727). [0003] Plants, the skin of red grapes, and other fruits produce resveratrol naturally. Certain glycosylated resveratrol species or resveratrol glycosides are also found in nature, in plants (mostly in grapevine plants, such as Vitis vinifera and Vitis pseudoreticulata, and mulberry plants). Methylated resveratrol species are also found in nature. For example, pterostilbene, a stilbenoid found in blueberries and grapes, is a double-methylated version of resveratrol that exhibits a higher bioavailability and is more resistant to degradation and elimination (Kapetanovic et al., 201 1, Cancer Chemother Pharmacol 68(3):593-60^. [0004] Known naturally occurring resveratrol glycosides include: c/s/frans-resveratrol-3- Ο-β- glucoside; resveratrol 3-0 - -D-glucopyranoside; piceid (Kirino et al., 2012, J Nutr Sci Vitaminol 58: 278-286; Larronde et al., 2005, Planta Med. 71: 888-890; Zhou et al., 2001 , Planta Med. 67: 158-61 ; Orsini et ai, 1997, J. Nat. Prod. 60: 1082-1087; Waffo-Teguo et ai, 1996, Phytochemistry 42: 1591-1593), c/s/frans-resveratrol-4'-0-3-glucoside; resveratroloside (Kirino et ai, 2012, J Nutr Sci Vitaminol 58: 278-286; Larronde et ai, 2005, Planta Med. 7 1: 888-890; Waffo-Teguo ef a/., 1998, J af. Prod. 61: 655-657), c/'s/frans-resveratrol-3,4'-di-0-3-glucoside; Mulberroside E (Larronde et ai, 2005, Planta Med. 7 1: 888-890; Decendit ef a/., 2002, Phytochemistry 60: 795-798; Zhou ef a/., 2001 , P/anfa /Wed. 67: 158-61 ; Hano ef ai, 1997, Ce/ . /Wo/. Z-/fe Sci. 53 : 237-241), c/'s/frans-resveratrol-3,5-di-0-3-glucoside (Larronde ef a/., 2005, Planta Med. 7 1: 888-890;); and c/s/frans-resveratrol-3,5,4'-tri-0- β-glucoside (Larronde ef a/., 2005, P/anfa Med. 71: 888-890). [0005] Resveratrol glycosides that have been produced in vitro or /'n /Vo include: trans- resveratrol-3-0-3-glucoside; piceid (Zhou ef ai, 2013, J . A/af. Prod. 76: 279-286; Hansen ef ai 2009, Phytochemistry 70: 473-482; Weis ef a/., 2006, nge . Chem. Int. Ed. 45: 3534-3538; Regev-Shoshani ef a/., 2003, Biochem J. 374: 157-163; Becker ef ai, 2003, FE/WS Yeasf Res. 4 : 79-85), frans-resveratrol-4'-0-3-glucoside; resveratroloside (Zhou ef a/., 2013, J A/af. Prod. 76: 279-286; Hansen ef ai, 2009, Phytochemistry 70: 473-482; Weis ef a/., 2006, nge . Chem. Int. Ed. 45: 3534-3538; Regev-Shoshani ef a/., 2003, Biochem J. 374: 157-163), frans- resveratrol-3,4'-di-0-3-glucoside; Mulberroside E (Zhou et ai, 2013, J. Nat. Prod. 76: 279-286), frans-glucosyl-a-(1-4)-piceid (Hyunsu ef a/., 2012, J. Microbiol. Biotechnol. 22: 1698-1704), frans-a-D-maltosyl-(1-4)-piceid (Park et al., 2012, J Agric. Food Chem. 60: 8183-8189). [0006] Generally, resveratrol is produced in plants and yeast through the phenylpropanoid pathway as illustrated by the reactions shown in Figures 1 and 2 and as described in U.S. 2008/0286844, which is incorporated by reference in its entirety herein. [0007] Present production processes rely mostly upon extraction of resveratrol, either from the skin of grape berries or from the plant, Fallopia japonica, known as "Japanese knotweed." Current extraction and purification methods use organic solvents to extract resveratrol and separate it from the biomass and/or cell debris. Examples of these solvents include, among others, ethanol, methanol, ethyl acetate, and petroleum ether. This is a labor-intensive process and generates low yields. Moreover, since resveratrol or its mono-glucosides (e.g., piceid and resveratroloside) have low water-solubility (see, e.g., Gao & Ming, 2010, Mini Rev Med Chem 10(6):550-67), it forms aggregates/crystals upon addition to water and/or formation by a recombinant resveratrol producing- and secreting-microorganism. Separation of resveratrol aggregates/crystals from recombinant or other cells (such as microorganisms or plant cells) by centrifugation is inefficient. [0008] In yeast, the starting metabolites are malonyl-CoA and phenylalanine or tyrosine (aromatic amino acids). The amino acid L-phenylalanine is converted into trans-cinnamic acid through non-oxidative deamination by L-phenylalanine ammonia lyase (PAL). Next, trans- cinnamic acid is hydroxylated at the para-position to 4-coumaric acid (4-hydroxycinnamic acid) by cinnamate-4-hydroxylase (C4H), a cytochrome P450 monooxygenase enzyme, in conjunction with NADPH:cytochrome P450 reductase (CPR). Alternatively, the amino acid L- tyrosine is converted into 4-coumaric acid by tyrosine ammonia lyase (TAL). The 4-coumaric acid from either alternative pathway is subsequently activated to 4-coumaroyl-CoA by the action of 4-coumarate-CoA ligase (4CL). Finally, stilbene synthase (STS), also known as resveratrol synthase (RS), catalyzes condensation of a phenylpropane unit of 4-coumaroyl-CoA with malonyl-CoA resulting in formation of resveratrol. [0009] Previously, a yeast strain was disclosed that could produce resveratrol from 4- coumaric acid that is found in small quantities in grape must (Becker et al., 2003, FEMS Yeast Res. 4 : 79-85). Production of 4-coumaroyl-CoA, and concomitantly resveratrol, in laboratory strains of Saccharomyces cerevisiae, has been achieved by co-expressing a heterologous coenzyme-A ligase gene from hybrid poplar, together with the grapevine resveratrol synthase gene (vstl) (Becker et al., 2003, FEMS Yeast Res.
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