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WO 2016/193504 Al 8 December 2016 (08.12.2016) P O P C T

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WO 2016/193504 Al 8 December 2016 (08.12.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2016/193504 Al 8 December 2016 (08.12.2016) P O P C T (51) International Patent Classification: (74) Agent: SMAGGASGALE, Gillian Helen; WP C12N 9/02 (2006.01) C12P 7/22 (2006.01) Thompson, 138 Fetter Lane, London EC4A 1BT (GB). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/EP20 16/0628 18 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) Date: International Filing BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 6 June 2016 (06.06.2016) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/171,742 5 June 2015 (05.06.2015) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/33 1,023 3 May 2016 (03.05.2016) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/337,576 17 May 2016 (17.05.2016) (84) Designated States (unless otherwise indicated, for every (71) Applicant: EVOLVA SA [CH/CH]; Duggingerstrasse 23, kind of regional protection available): ARIPO (BW, GH, 4153 Reinach (CH). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors: NAESBY, Michael; 2, Rue de l'Hotel de Ville, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 68330 Huningue (FR). SIMON VECILLA, Ernesto; DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Brandbyvestervej 15 st th, 2600 Glostrup (DK). EICHEN- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, BERGER, Michael; Gilgenbergerstrasse 23, 4053 Basel SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (CH). LEHKA, Beata Joanna; Landlystvej 10,1 th, 2500 GW, KM, ML, MR, NE, SN, TD, TG). Valby Copenhagen (DK). BJ0RN-YOSHIMOTO, Walden Emil; c/o Evolva SA, Duggingerstrasse 23, 4153 Published: Reinach (CH). JENSEN, Niels Bjerg; Karupvej No. 8, — with international search report (Art. 21(3)) 2770 Kastrup (DK). DYEKJ^R, Jane Dannow; J.A. — with sequence listing part of description (Rule 5.2(a)) Schwartz Gade 34, DK-2100 Copenhagen (DK). © (54) Title: BIOSYNTHESIS OF PHENYLPROPANOID AND DIHYDROPHENYLPROPANOID DERIVATIVES © (57) Abstract: Provided herein are methods and compositions for producing phenylpropanoid derivatives, such as chalcones and stilbenes, and dihydrophenylpropanoid derivatives, such as dihydrochalcones and dihydrostilbenes, in microorganisms. In particular, the disclosure provides recombinant microorgamsms and methods of use thereof for producing phenylpropanoid derivative com pounds and dihydrophenylpropanoid derivative compounds. BIOSYNTHESIS OF PHENYLPROPANOID AND DIHYDROPHENYLPROPANOID DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/171,742, filed June 5, 2015, U.S. Provisional Application No. 62/331,023, filed May 3 , 2016, and U.S. Provisional Application No. 62/337,576, filed May 17, 2016, the disclosures of each of which are hereby incorporated by reference in their entireties. BACKGROUND Field of the Invention [0002] Provided herein are methods and compositions for biosynthetic production of compounds in host organisms. In particular, the disclosure relates to biosynthetic production of phenylpropanoid derivative compounds, such as chalcones and stilbenes, and of dihydrophenylpropanoid derivative compounds, such as dihydrochalcones and dihydrostilbenes. Description of Related Art [0003] Phenylpropanoids are a diverse family of phenolic compounds produced biosynthetically in plants from phenolic amino acid precursors. Phenylpropanoids and their derivatives have desirable applications, for example in the food and healthcare industries. [0004] An exemplary phenylpropanoid derivative is naringenin, a compound that is also an intermediate in the production of downstream phenylpropanoid derivatives. Naringenin has the chemical structure: [0005] Naringenin is produced naturally in plants, and also biosynthetically in cells genetically engineered with components of a flavonoid biosynthesis pathway (see e.g., Koopman et ai, (2012) Microbial Cell Factories 2012, 11:155). For example, cells engineered to produce coumaroyl-CoA are further engineered with recombinant genes expressing proteins that convert coumaroyl-CoA to naringenin. [0006] Another exemplary phenylpropanoid derivative is the stilbene resveratrol, which is also an intermediate in the production of other downstream phenylpropanoid derivatives. Resveratrol has the chemical structure: [0007] Resveratrol is also produced using a coumaroyl-CoA precursor molecule.Dihydrophenylpropanoids are phenylpropanoid derivatives wherein the double bond of the phenylpropanoid propene tail is reduced. Dihydrophenylpropanoids, such as dihydrocoumaroyl-CoA or dihydrocinnamoyl-CoA, provide important biosynthetic intermediates in the production of various desirable compounds, for example members of the dihydrochalcones and members of the dihydrostilbenoids. [0008] Examples of dihydrostilbenoids are dihydroresveratrol and dihydropinosylvin, which are produced by stilbene synthase (STS)-catalyzed conversion of dihydrocoumaroyl- CoA or dihydrocinnamoyl-CoA respectively, and which are represented by the following chemical structures: (dihydropinosylvin). [0009] The amorfrutins are another class of dihydrophenylpropanoid-derived dihydrostilbenoid plant compounds with potential health benefits. See, e.g., Sauer, Chembiochem 2014, 15(9):1231-8. An example of an amorfrutin is amorfrutin 2 , which is represented by the following chemical structure: [0010] An example of a dihydrochalconoid compound is phlorizin. Phlorizin occurs in nature in some plants, including pear, apple, cherry, and other fruit trees. Phlorizin has been shown to inhibit Sodium/Glucose Cotransporter 1 (SGLT1) and Sodium/Glucose Cotransporter 2 (SGLT2), involved in glucose reabsorption from the intestine and liver. Accordingly, phlorizin has potential uses for controlling blood sugar levels, e.g., prevention of hyperglycemia in connection with Type 2 diabetes, as well as other potential uses to improve human health. Phlorizin is represented by the following chemical structure: (phlorizin). [001 ] Another example of a dihydrophenylpropanoid derivative is the biosynthetic precursor for phlorizin, called phloretin (phlorizin is a 2'-glucoside of phloretin). Phloretin shares some of the same properties as phlorizin, including, for example, the ability to inhibit active transport of SGLT1 and SGLT2. Additionally, phloretin has been found to inhibit Glucose Transporter 2 (GLUT2). Phloretin is represented by the following chemical structure: (phloretin). [0012] One step of the biosynthetic pathways for both dihydrochalcones (such as phloretin and phlorizin) and dihydrostilbenes is the conversion of a phenylpropanoid (e.g., p- coumaroyl-CoA) to a dihydrophenylpropanoid (e.g., p-dihydrocoumaroyl-CoA). Recombinant hosts engineered for p-coumaroyl-CoA biosynthesis are known in the art (See e.g. U.S. Patent No. 8,343,739). However, there remains a need for the recombinant conversion of phenylpropanoids to dihydrophenylpropanoids. [0013] In addition, current methods of producing naringenin, resveratrol, and other phenylpropanoid derivatives are limited by pathways that compete for phenylpropanoids such as coumaroyl-CoA as a substrate. For example, it is known that certain cells engineered to produce naringenin also produce phloretic acid by an unknown mechanism (see e.g., Koopman et al., (2012) Microbial Cell Factories 2012, 1 :155). Phloretic acid is a dihydro-phenylpropanoid, and one step of the biosynthetic pathways for dihydrophenylpropanoid production is the conversion of a phenylpropanoid (e.g., p- coumaroyl-CoA) to a dihydrophenylpropanoid (e.g., p-dihydrocoumaroyl-CoA). However, the enzymes responsible for producing dihydrophenylpropanoids (and reducing, for example, naringenin production) are unknown. Accordingly, there is a need in the art for optimized production of phenylpropanoid derivatives such as naringenin in recombinant host cells. SUMMARY [0014] The methods and compositions disclosed herein are not limited to specific advantages or functionality. [0015] In one aspect, the disclosure provides methods of modulating production of a phenylpropanoid derivative compound relative to a dihydrophenylpropanoid derivative compound in a recombinant host cell, the methods comprising: (a) increasing production of the phenylpropanoid derivative compound relative to the dihydrophenylpropanoid derivative compound by reducing or eliminating (i) double-bond reductase activity, or (ii) expression of a gene encoding a double-bond reductase polypeptide; or (b) decreasing production of the phenylpropanoid derivative compound relative to the dihydrophenylpropanoid derivative compound by increasing (i) double-bond reductase activity, or (ii) expression of a gene encoding a double-bond reductase polypeptide; wherein the phenylpropanoid derivative compound is a chalcone or stilbene, and wherein the dihydrophenylpropanoid derivative compound is a dihydrochalcone or dihydrostilbene. In some embodiments, the double-bond reductase polypeptide
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