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WO 2011/094457 Al (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 ι 4 August 2011 (04.08.2011) WO 201 1/094457 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12P 7/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US201 1/022790 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 27 January 201 1 (27.01 .201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/298,844 27 January 2010 (27.01 .2010) US (84) Designated States (unless otherwise indicated, for every 61/321,480 6 April 2010 (06.04.2010) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (71) Applicants (for all designated States except US): OPX ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, BIOTECHNOLOGIES, INC. [ /US]; 2425 55th TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Street, Suite 100, Boulder, CO 80301 (US). THE RE¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, GENTS OF THE UNIVERSITY OF COLORADO, A LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, BODY CORPORATE [US/US]; 1800 Grant Street, 8th SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Floor, Denver, CO 80203 (US). GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and Published: (75) Inventors/ Applicants (for US only): LYNCH, Michael, — with international search report (Art. 21(3)) D. [US/US]; 2425 55th Street, Suite 101, Boulder, CO 80301 (US). GILL, Ryan, T. [US/US]; 2025 Ash Street, — before the expiration of the time limit for amending the Denver, CO 80207 (US). WARNECKE-LIPSCOMB, claims and to be republished in the event of receipt of Tanya [US/US]; 760 32nd Street, Boulder, CO 80303 amendments (Rule 48.2(h)) (US). — with sequence listing part of description (Rule 5.2(a)) (74) Agent: FISCHER, Joseph; OPX Biotechnologies, Inc., 2425 55th Street, Suite 100, Boulder, CO 80301 (US). (54) Title: MICROORGANISM PRODUCTION OF HIGH-VALVE CHEMICAL PRODUCTS, AND RELATED COMPOSI TIONS, METHODS AND SYSTEMS J © o (57) Abstract: This invention relates to metabolically engineered microorganism strains, such as bacterial strains, in which there is an increased utilization of malonyl-CoA for production of a chemical product, which includes polyketides and 3-hydroxypropi- onic acid. MICROORGANISM PRODUCTION OF HIGH-VALUE CHEMICAL PRODUCTS, AND RELATED COMPOSITIONS, METHODS AND SYSTEMS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Application 61/298,844, filed January 27, 2010, and U.S. Provisional Application 61/321,480, filed April 6, 2010. The entire contents of each application are hereby incorporated by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED DEVELOPMENT [0002] This invention was made with Government support under DE-AR0000088 awarded by the United States Department of Energy, and with Government support under grants BES0228584 and BES0449183 awarded by the National Science Foundation. The Government has certain rights in this invention. FIELD OF THE INVENTION [0003] This invention relates to metabolically engineered microorganisms, such as bacterial strains, in which there is an increased utilization of malonyl-CoA for production of a chemical product, which may include polyketide chemicals. Also, genetic modifications may be made to provide one or more chemical product, such as polyketide, biosynthesis pathways in microorganisms. SEQUENCE LISTING [0004] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS- Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 27, 201 1, is named OPXX201 11 and is 2,236,123 bytes in size. BACKGROUND OF THE INVENTION [0005] With increasing acceptance that petroleum hydrocarbon supplies are decreasing and their costs are ultimately increasing, interest has increased for developing and improving industrial microbial systems for production of chemicals and fuels. Such industrial microbial systems could completely or partially replace the use of petroleum hydrocarbons for production of certain chemicals. [0006] Numerous chemicals are produced through such means, ranging from antibiotic and anti-malarial pharmaceutical products to fine chemicals to fuels such as ethanol. Commercial objectives for microbial fermentation include the increase of titer, production rate, and yield of a target chemical product. When the overall specific productivity in a fermentation event is elevated, this may positively affect yield in addition to production rate and other economic factors, such as capital costs. [0007] One candidate chemical for such production is 3-hydroxypropionic acid ("3-HP", CAS No. 503-66-2), which may be converted to a number of basic building blocks for polymers used in a wide range of industrial and consumer products. Unfortunately, previous efforts to microbially synthesize 3-HP to achieve commercially viable titers have revealed that the microbes being used were inhibited by concentrations of 3-HP far below a determined commercially viable titer. [0008] Other chemicals of interest include various chemicals that have malony-CoA as a substrate in one or more enzymatic conversion steps. [0009] In spite of strong interest to improve microbial fermentation economics by improving yield and/or productivity for certain chemical products, there remains a need to increase net conversion, as may be quantified by yield over various periods of or an entire fermentation production run, in a fermentative microorganism cell to desired target chemical products employing commercially viable fermentation methods. Additionally, among related problems remaining to be solved are how to improve specific productivity and volumetric productivity, such as to economically important levels, in modified microorganisms that are adapted to produce a chemical product having malonyl-CoA as a substrate in the microbial production pathway of that chemical product, such as but not limited to various polyketide chemical products. SUMMARY OF THE INVENTION [0010] According to one embodiment, the invention is directed to a method for producing a chemical product, such as a polyketide, said method comprising i) combining a carbon source and a microorganism cell culture to produce such chemical product, wherein a) said cell culture comprises an inhibitor of fatty acid synthase or said microorganism is genetically modified for reduced enzymatic activity in the organism' s fatty acid synthase pathway, providing for reduced conversion of malonyl-CoA to fatty acids; and b) wherein said chemical product is a polyketide produced by said microorganism via a metabolic pathway from malonyl-CoA to the polyketide chemical product. This may include embodiments wherein said microorganism is genetically modified for increased enzymatic activity in the organism' s chemical product biosynthesis pathway, which includes malonyl-CoA as an intermediate (i.e., as a substrate in one of the biosynthesis enzymatic conversion steps). [0011] In another embodiment, the invention is directed to a method for producing a chemical product, such as a polyketide, said method comprising i) combining a carbon source and a microorganism cell culture to produce such chemical product, wherein a) said cell culture comprises an inhibitor of fatty acid synthase or said microorganism is genetically modified for reduced enzymatic activity in the organism' s fatty acid synthase pathway, providing for reduced conversion of malonyl-CoA to fatty acids; and b) wherein said chemical product is produced by said microorganism via a genetic modification introducing a metabolic pathway from malonyl-CoA to the chemical product. In some such embodiments, the chemical product is not 3- hydroxypropionic acid or an acrylic-based consumer product made there from. [0012] In various aspects, the carbon source has a ratio of carbon-14 to carbon-12 of about 1.0 x 10 14 or greater. Also, for any of the above embodiments, the carbon source is predominantly glucose, sucrose, fructose, dextrose, lactose, a combination thereof, or wherein said carbon source is less than 50% glycerol. Also, in various embodiments of the above methods the microorganism is genetically modified for increased enzymatic activity of one or more enzymatic conversion steps from malonyl-CoA to the chemical product, and some such embodiments at least one polynucleotide is provided into the microorganism cell that encodes a polypeptide that catalyzes a conversion step along the metabolic pathway. [0013] In some of the above embodiments, the cell culture comprises an inhibitor of fatty acid synthase or said microorganism is genetically modified for reduced enzymatic activity in the organism' s fatty acid synthase pathway. In some of the latter embodiments, the inhibitor of a fatty acid synthase is selected from the group consisting of thiolactomycin,
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