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C12) United States Patent (IO) Patent No.: US 10,774,349 B2 San Et Al

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C12) United States Patent (IO) Patent No.: US 10,774,349 B2 San Et Al I1111111111111111 1111111111 111111111111111 IIIII IIIII IIIII IIIIII IIII IIII IIII US010774349B2 c12) United States Patent (IO) Patent No.: US 10,774,349 B2 San et al. (45) Date of Patent: Sep.15,2020 (54) ALPHA OMEGA BIFUNCTIONAL FATTY 9/1029 (2013.01); C12N 9/13 (2013.01); ACIDS C12N 9/16 (2013.01); C12N 9/88 (2013.01); C12N 9/93 (2013.01) (71) Applicant: William Marsh Rice University, (58) Field of Classification Search Houston, TX (US) None See application file for complete search history. (72) Inventors: Ka-Yiu San, Houston, TX (US); Dan Wang, Houston, TX (US) (56) References Cited (73) Assignee: William Marsh Rice University, U.S. PATENT DOCUMENTS Houston, TX (US) 9,994,881 B2 * 6/2018 Gonzalez . Cl2N 9/0006 2016/0090576 Al 3/2016 Garg et al. ( *) Notice: Subject to any disclaimer, the term ofthis patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 152 days. WO W02000075343 12/2000 (21) Appl. No.: 15/572,099 WO W02016179572 11/2016 (22) PCT Filed: May 7, 2016 OTHER PUBLICATIONS (86) PCT No.: PCT/US2016/031386 Choi, K. H., R. J. Heath, and C. 0. Rock. 2000. 13-Ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in § 371 (c)(l), branched-chain fatty acid biosynthesis. J. Bacteriol. 182:365-370. (2) Date: Nov. 6, 2017 He, X., and K. A. Reynolds. 2002. Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl (87) PCT Pub. No.: WO2016/179572 carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob. Agents Chemother. 46:1310-1318. PCT Pub. Date: Nov. 10, 2016 Qiu, X, et al., Crystal structure and substrate specificity of the b-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylo­ (65) Prior Publication Data coccus aureus, Protein Science (2005), 14:2087-2094 (2005). Wu et al. "Efficient odd straight medium chain free fatty acid US 2018/0119183 Al May 3, 2018 production by metabolically engineered Escherichia coli," Biotechnol Bioeng. Jul. 14, 2014 (Jul. 14, 2014), vol. 111, pp. 2209-2219. Related U.S. Application Data Traavik et al. "Chapter 4:Genetic Engineering of Living Cells and (60) Provisional application No. 62/158,413, filed on May Organisms," Biosafety First, Ed.Traavik, 2007, pp. 1-23. 7, 2015. * cited by examiner (51) Int. Cl. C12P 7164 (2006.01) Primary Examiner - Suzanne M Noakes CllB 1100 (2006.01) Assistant Examiner - Jae W Lee C12N 9/10 (2006.01) (74) Attorney, Agent, or Firm - Boulware & Valoir C12N 9/16 (2006.01) C12N 9/88 (2006.01) (57) ABSTRACT C12N 9/00 (2006.01) The present disclosure describes an engineered microorgan­ CllC 1100 (2006.01) ism for producing alpha omega bifunctional C6-l 6 fatty (52) U.S. Cl. acids from renewable carbon sources. CPC .............. C12P 716409 (2013.01); CllB 1100 (2013.01); CllC 11002 (2013.01); C12N 15 Claims, 4 Drawing Sheets e• 00 • Gfuco-S"e ~ ~ ~ ~ PEP a, lu carboxylic acids =~ ! ~ Pyruvat~-.._ Acetate AlkJ,ALKH rJJ ('D ! ,L__ Ace, Fa~~- '? Ac c A --- .... "',,-t'<lf O ..............•r•• ; v '"Ul ~ ......... ................ IKA"'ll! '\ l _ fatty acids i N {✓------..,Glycolyl Cofy l w-Hydroxy- i 0 j N '--·-~--.,_,,,..,.,. l i 0 OAA --...__ i : rACP- : ,- " P,pE/Pd ! Acyl-ACP SH i F Citrate ! TE .,.,,_,; Mafate,._ AceB \AtGLY: Glycolate L......,.............. ....... Mafonyl-ACP / r,· Glyoxylate, -t, N.AD+ Acy - ! rJJ 1 ·-~~ ('D=­ Fumarate~AceA lso~ate l ·r-\""'I Fao81F CO +ACP ('D . 1 - led ' NADH _J "' ' ......... 0 \ at a-hetogluta,ate ! Hyd,oxyl Fatty 3-<-aeyi-CoAJACP .... Succm" Succinyl-. .. CAo / l Enoyl-CoAfA. CP acid efongat/onV::. NADPH .i;... , ~ ccle l H F h.G 'l . 2 Fe!JZ 60, NADP l 3--Hydro,xyacyl- l lt CoAiACP l d t rJl. ""'"' GtycoJate '"=--..l --..l ~ FIGURE 1 w ~ \0 =N U.S. Patent Sep.15,2020 Sheet 2 of 4 US 10,774,349 B2 au (IJ uI !i,.. I­ C.. a:: 0.. E <( U.S. Patent Sep.15,2020 Sheet 3 of 4 US 10,774,349 B2 I'-,., r§ l,:1 8?"-T § e• 00 • FIGURE4 ~ ~ Prirning molecules ~ Externally ~ added )I Glycolate =~ Beta--abnine CoA synthetase rJJ Acrylic add CoA transferase ('D '? Pathway(s) to etc -------1 Activated .... '"Ul syntheSize the N pnmmg 0 Carbon N pnrnmg 0 ➔" I ......... ............. ......................... ➔ I ff~olec:utes I source ,molecules rJJ Introduce pathvJay{s) to ('D=­ ('D v;,.c 'In r Acetyl-CoA .... the eng]neered strain ~::t•tl .i;... 0.... .i;... ~ Omega hvdroxv fatty acid fatty add O ,e,n,pg·:?, ,.,rnino tatty acid . I :t: t ;F '-" G C! ' " ' ·. , <............ ···· ···· ·SSH!iUUH1HH1HH1 elongation d On1ega unsaturated fatty acici I Termination r.,;_ cycle etc "'""' -..=-....l -....l final product w~ ~ \0 =N US 10,774,349 B2 1 2 ALPHA OMEGA BIFUNCTIONAL FATTY (encoded by fabG), 3-hydroxyacyl-ACP dehydratase (en­ ACIDS coded by fabA), and enoyl-ACP reductase (encoded by fabI). PRIOR RELATED APPLICATIONS In the type II fatty acid synthase system, there are three 5 genetically and biochemically distinct KAS isomers, namely This application is a National Phase under 35 U.S.C. KASI (encoded by fabB), KASH (encoded by fabF), and § 371 of International Application PCT/US16/31386, filed KASIII (encoded by fabH). Their functions have been May 7, 2016, which claims priority to U.S. Ser. No. 62/158, studied extensively in E. coli. They differ in their specifici­ 413 filed May 7, 2015. Both applications are expressly ties for acyl-thioester substrates, having optimum activities 10 for substrates of different acyl-chain lengths and different incorporated by reference herein in their entirety for all thioesters. While KASI and KASH catalyze the condensa­ purposes. tion between acyl-ACP (of longer acyl-chain length) with malonyl-ACP substrates, KASIII specifically utilizes acetyl­ FEDERALLY SPONSORED RESEARCH CoA as a substrate for the condensing reaction with malo- STATEMENT 15 nyl-ACP, and thus initiates fatty acid biosynthesis. In this disclosure, summarized in FIG. 4, we demonstrate This invention was made with government support under the production of omega functionalized fatty acids by engi­ Grant No: EEC-0813570 awarded by the NSF. The govern­ neering bacteria to have an overexpressed KASIII enzyme ment has certain rights in the invention. with substrate specificity such that it can convert: 20 FIELD OF THE DISCLOSURE R -CH2(0-n)CO-CoA + malonyl-[ACP] + Ir .... This invention relates generally to a microbial method to synthesize bifunctional short- to medium-carbon chain R-CH2(0-n)COCH2CO-[ACP] + CO2 + Co-A length fatty acids, in particular, alpha-omega bifunctional 25 fatty acids, such as, omega hydroxyl fatty acids. wherein R is a functional group, including a hydroxy, amine, branch, carboxyl, double bond, a benzoyl group, BACKGROUND OF THE DISCLOSURE a cyclic group, a halogen group, and the like. n=0 to 10, and can be changed by chaining the TE. Hydroxy fatty acids are widely used for making polymers 30 The remaining FAS enzymes are used to grow the omega and are also valuable in chemical, cosmetic and food indus­ functionalized fatty acid, and a TE with the desired length tries as starting materials for synthesis of lubricants, adhe­ preference is also overexpressed and can free the resulting sives, and cosmetic ingredients. Similarly, dicarboxylic fatty omega-functionalized fatty acid. Preferably, the microbe is acids have many industrial applications, such as synthesis of also engineered to make the desired R----CH 2 co-n)CO-CoA copolymers like polyamides and polyesters, coatings, adhe­ 35 starting material. In this way, the can be grown on standard sives, greases, polyesters, dyestuffs, detergents, flame retar­ carbon sources, such as glycerol, glucose, sucrose, fructose, dants, cosmetic ingredients, and fragrances. For example, inositol, arabitol, xylose, cellulose, saccharose, as well as on adipic acid (n=6) is among the top 50 bulk manufactured waste resources such as com steep liquor, and the like. If chemicals in US, and primarily used for manufacturing desired, the resulting omega functionalized fatty acid can be nylon. Sebacic acid (n=S) and its derivatives have many 40 further converted to other desirable products. applications and are used in manufacturing plasticizers, By "omega", herein, we refer to the end of the growing lubricants, and cosmetics. Dodecanedioic acid (n=12) is straight chain fatty acid opposite the ACP. The nomeculature used in the production of nylon (nylon-6,12) and poly­ remains even after cleavage from the ACP. Thus, the last amides. carbon in the growing straight chain is the omega position. Hydroxy fatty acids and dicarboxylic fatty acids are 45 In this molecule, for example, the hydroxyl is on the omega typically produced by a chemical process, or microbial carbon, while the alpha carbon is the carboxylate: transformation of aliphatic hydrocarbons and fatty acids. OH-----CH -----CH -----CH -----CH -----COOH omega-hy­ However, it would be of benefit to make these valuable 2 2 2 2 droxy buytrate chemicals starting with common, renewable carbon sources, such as glucose, glycerol, and the like. 50 Two separate approaches have been demonstrated using the production of omega hydroxy fatty acid as examples. SUMMARY OF THE DISCLOSURE In the first approach, omega hydroxy fatty acid (specifi­ cally 16-hydroxyhexanoic acid) was produced by the meta­ The biochemical mechanism of fatty acid biosynthesis is bolically engineered strain by adding glycolate for use as a universally similar among all organisms. Generally, fatty 55 recursor to the initiating primer for fatty acid synthesis and acids are synthesized by the repeated iteration of four­ using an acyl-ACP thioesterase (TE) from Ricinus commu- reactions, which start with an acyl-COA primer, which is nis. elongated, two carbons per cycle, using carbon atoms In second approach, the strains were further engineered to derived from a malonyl moiety.
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