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(12) United States Patent (10) Patent No.: US 9,169.496 B2 Marliere (45) Date of Patent: Oct

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(12) United States Patent (10) Patent No.: US 9,169.496 B2 Marliere (45) Date of Patent: Oct US009 169496B2 (12) United States Patent (10) Patent No.: US 9,169.496 B2 Marliere (45) Date of Patent: Oct. 27, 2015 (54) METHOD FOR THE ENZYMATIC (2013.01); C12N 9/1235 (2013.01); C12N 9/88 PRODUCTION OF BUTADIENE (2013.01); CI2P 7/04 (2013.01); C12P 7/24 (2013.01) (71) Applicant: Scientist of Fortune, S.A., Luxembourg (58) Field of Classification Search (LU) None See application file for complete search history. (72) Inventor: Philippe Marliere, Mouscron (BE) (56) References Cited (73) Assignee: Scientist of Fortune, S.A., Luxembourg (LU) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 5,855,881. A * 1/1999 Loike et al. .................. 424.942 patent is extended or adjusted under 35 2011/0300597 A1* 12/2011 Burk et al. .................... 435/167 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 14/352,825 WO 2009111513 A1 9, 2009 WO 2011 14.0171 A 11, 2011 (22) PCT Filed: Oct. 18, 2012 (Continued) (86). PCT No.: PCT/EP2012/07O661 OTHER PUBLICATIONS S371 (c)(1), EC 1.1.1.34 (last viewed on Mar. 30, 2015).* (2) Date: Apr. 18, 2014 (Continued) (87) PCT Pub. No.: WO2013/057.194 Primary Examiner — Alexander Kim PCT Pub. Date: Apr. 25, 2013 (74) Attorney, Agent, or Firm — Michael M. Wales; InHouse Patent Counsel, LLC (65) Prior Publication Data (57) ABSTRACT US 2014/0256009 A1 Sep. 11, 2014 Described is a method for the enzymatic production of buta diene which allows to produce butadiene from crotyl alcohol. Related U.S. Application Data Also described are enzyme combinations and compositions (60) Provisional application No. 61/549,149, filed on Oct. containing Such enzyme combinations which allow the enzy 19, 2011. matic conversion of crotyl alcohol into butadiene. Further more, the invention relates to microorganisms which have (30) Foreign Application Priority Data been genetically modified so as to be able to produce butadi ene from crotyl alcohol. Oct. 19, 2011 (EP) ..................................... 11185854 Moreover, the invention relates to a method for the enzymatic production of crotyl alcohol from crotonyl-Coenzyme A. The (51) Int. Cl. obtained crotyl alcohol can be further converted into butadi CI2P 5/02 (2006.01) ene as described herein. Also described are enzyme combi CI2P 7/04 (2006.01) nations which allow to convert crotonyl-Coenzyme A into (Continued) crotyl alcohol as well as (micro)organisms which express (52) U.S. Cl. Such enzyme combinations. CPC ............... CI2P5/026 (2013.01); C12N 9/1205 32 Claims, 10 Drawing Sheets N-1s US 9,169.496 B2 Page 2 (51) Int. Cl. Osterman et al., Characterization of mutation-induced changes in the CI2P 7/24 (2006.01) maize (Zea may’s L.) ADH1-1S1108 alcoholdehydrogenase, Journal CI2N 9/12 (2006.01) Biochem. Genet. (1993), vol. 31 (11-12), pp. 497-506. Copy pro CI2N 9/88 (2006.01) vided with the Abstract only.* XP 0.08660506.1 (last viewed on Mar. 31, 2015).* (56) References Cited International Preliminary Examination Report (IPER) for PCT/ EP2012/070661 mailed on May 1, 2014. FOREIGN PATENT DOCUMENTS Database CAPLUS Online Chemical Abstracts Service; 1958, Gorin, Y.A. et al.: “Diene hydrocarbons from unsaturated alcohols. I. WO 2012081723 A1 6, 2012 Catalytic dehydration of crotyl alcohol to butadiene'. XP002673746, WO 2012106516 A1 8, 2012 Database accession No. 1958:72071. WO 2012177710 A1 12/2012 Database WPI Week 198927 Thomson Scientific, London, GB: AN OTHER PUBLICATIONS 1989-195596 XP002673747, & JP 1 132391 A (Showa Denko KK) May 24, 1989. EC 1.1.1.1. (last viewed on Mar. 30, 2015).* Database WPI Week 201244 Thomson Scientific, London, GB: AN EC 1.2.1n2 (last viewed on Mar. 30, 2015).* 2012-HO2951 XP002694246, & WO 2012/081723 A1 (Mitsubishi Q08891-FACR2 ARATH (last viewed on Mar. 30, 2015).* Chem Corp) Jun. 21, 2012. Q96533-ADHX ARATH (last viewed on Mar. 30, 2015).* Havel, C. AL. Isopentenoid synthesis in isolated embryonic Q9SAH9-CCR2 ARATH (last viewed on Mar. 30, 2015).* Q60352-IPK METJA (last viewed on Mar. 30, 2015).* Drosophila cells. Possible regulation of 3-hydroxy-3-methylglutaryl Q58270-IDSA METJA (last viewed on Mar. 30, 2015).* coenzyme A reductase activity by shunted mevalonate carbon, Jour Q60337-THIL METJA (last viewed on Mar. 30, 2015).* nal of Biological Chemistry, Aug. 5, 1986, pp. 10150-10156, vol. Lin et al., Characterization of the monoterpene synthase genetps26, 261, No. 22, XPO08160854. the ortholog of a gene induced by insect herbivory in maize. Plant Physiol. (2008), vol. 146(3), pp. 940-951.* * cited by examiner U.S. Patent Oct. 27, 2015 Sheet 1 of 10 US 9,169.496 B2 1S-1Noh Figure 1 O O O I 1s-1No-Noh -1S-1N1 Yo1">oh O H OH OH Figure 2 -1S-1SO Figure 3 N-1s Figure 4 U.S. Patent Oct. 27, 2015 Sheet 2 of 10 US 9,169.496 B2 L-Lactate NAD" Lactate dehydrogenase 340 nm. Crotyl alcohol ATP Pyruvate NADH Studied enzyme C Pyruvate kinase Crotyl phosphate ADP Phosphoenolpyruvate Figure 5 iss MY -RS, (8-08.pnin (38-48 51.2 426,5 484.5454. SSS 225,3 f isis ls....l...bulli t 1. 28 3. 4) wo fig Figure 6 U.S. Patent Oct. 27, 2015 Sheet 3 of 10 US 9,169.496 B2 tes, As. 5-0.7 rain i{27-33) 80 44 230 Figure 7 O O P P OH 2 * ...Ho1 -N-N Yo1 | SOH OH OH OH OH Dimethylallyl diphosphate isoprene Diphosphate P P 4\-1 Ho1 OHNo1 OHNoh Croty diphosphate 1,3-Butadiene Diphosphate Figure 8 U.S. Patent Oct. 27, 2015 Sheet 4 of 10 US 9,169.496 B2 NNH O H OH A Q l Qan (...)A e -s-s-s-N-N- -N-frogSofo, : N Ö o O O k OH Og-Ps O -- Figure 9 2126 Crotyl monophosphate Crotyl diphosphate 2OO 53.3 1513 ---235) 1CO 79.193.1 120.3 10 Figure 10a U.S. Patent Oct. 27, 2015 Sheet 5 of 10 US 9,169.496 B2 liters. Crotyl monophosphate 27 No croty diphosphate AO 154 3CO 9. 20 O 93. 34.3 244, 9 - t l 20 300 Figure 10b 118 y 120 E s st- 1 OO 30 li c t s Nt 6O i : 42 atC. 40 12 - : 20 O 1 45r Withiott (E)-beta isoprene Monoterpene Monoterpene enzyme ocimene synthase P. synthase E. synthaser it. synthase W. montana war. globulus alternifolia Winifera Obata Figure 11 U.S. Patent Oct. 27, 2015 Sheet 6 of 10 US 9,169.496 B2 ------------------ saw |||( || U.S. Patent US 9,169.496 B2 92 qz),aun61-I U.S. Patent Oct. 27, 2015 Sheet 8 of 10 US 9,169.496 B2 16?|||| Z U.S. Patent Oct. 27, 2015 Sheet 9 of 10 US 9,169.496 B2 ?7),aun61-I U.S. Patent Oct. 27, 2015 Sheet 10 of 10 US 9,169.496 B2 s al i US 9, 169,496 B2 1. 2 METHOD FOR THE ENZYMATIC metabolic intermediate acetyl-Coenzyme A (in the following PRODUCTION OF BUTADIENE acetyl-CoA) as described herein. Thus, in a first aspect, the present invention relates to a This Application is a 371 National Phase filing of EP process for the production ofbutadiene in which butadiene is 2012070661 filed Oct. 18, 2012, which is a continuation of 5 produced by the enzymatic conversion of crotyl alcohol. Cro EP 11 858 544 which was filed on Oct. 19, 2011 and a tyl alcohol, also referred to as crotonyl alcohol or crotonol, is nonprovisional of U.S. Ser. No. 61/545,149 filed Oct. 19, an unsaturated alcohol of formula CHO (see FIG. 1). 2011, which are all incorporated by reference in their entirety. Another name for crotyl alcohol is But-2-en-1-ol. It can be The present invention relates to a method for the enzymatic produced by reduction of crotonaldehyde (see FIG. 3). 10 According to the present invention crotyl alcohol can be production of butadiene which allows to produce butadiene converted into butadiene by enzymatic reactions involving as from crotyl alcohol. The present invention also relates to intermediates crotyl phosphate and/or crotyl diphosphate. microorganisms which have been genetically modified so as Thus, the principle underlying the present invention is that to produce butadiene. crotyl alcohol is first enzymatically activated by the conver The present invention also relates to a method for the 15 sion into crotyl phosphate or crotyl diphosphate and is then enzymatic production of crotyl alcohol from crotonyl-Coen further converted into butadiene by the use of appropriate Zyme A. The obtained crotyl alcohol can be further converted enzymes as described below. into butadiene as described herein. The present invention Thus, the present invention relates, in a first aspect, to a furthermore relates to enzyme combinations which allow to method for the production ofbutadiene comprising the enzy convert crotonyl-Coenzyme A into crotyl alcohol as well as to matic conversion of crotyl alcohol into butadiene via crotyl (micro)organisms which express Such enzyme combinations. phosphate or crotyl diphosphate. Butadiene (1,3-butadiene) is a conjugated diene with the The enzymatic conversion of crotyl alcohol into butadiene formula CH (see FIG. 4). It is an important industrial can occur via different alternative routes. In a first aspect (A), chemical used as a monomer in the production of synthetic the present invention relates to a method for the production of rubber. There exist different possibilities to produce butadi 25 butadiene comprising the enzymatic conversion of crotyl ene. Butadiene is, for example, produced as a by product of alcohol into butadiene via crotyl phosphate wherein said the steam cracking process used to produce ethylene and method comprises the steps of other olefins.
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