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(12) United States Patent (10) Patent No.: US 8.420,375 B2 (US) 336 a 3

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(12) United States Patent (10) Patent No.: US 8.420,375 B2 (US) 336 a 3 USOO8420375B2 (12) United States Patent (10) Patent No.: US 8.420,375 B2 Osterhout et al. (45) Date of Patent: Apr. 16, 2013 (54) MICROORGANISMS AND METHODS FOR 5,487.987 A 1/1996 Frost et al. CARBON-EFFICIENT BOSYNTHESIS OF 559: A : 3: St. MEK AND 2-BUTANOL 5,573.931 A 11/1996 Guettler et al. 5,616,496 A 4/1997 Frost et al. (75) Inventors: Robin E. Osterhout, San Diego, CA 5,686,276 A 11/1997 Lafendet al. (US); Wei Niu, San Diego, CA (US); 5,700.934. A 12/1997 Wolters et al. Anthony P. Burgard, Bellefonte, PA 5,770.435 A 6/1998 Donnelly et al. (US) 336 A 3-86 SE,ghiem et al. 5,908,924 A 6/1999 Burdette et al. (73) Assignee: Genomatica, Inc., San Diego, CA (US) 5,958,745 A 9/1999 Gruys et al. 6,117,658 A 9, 2000 Dennis et al. (*) Notice: Subject to any disclaimer, the term of this 6,133,014 A 10/2000 Mukouyama et al. patent is extended or adjusted under 35 & S. A 1939: SEF, 1 U.S.C. 154(b) by 202 days. 6,194.572k --- B1 2/2001 Buijsonnelly et al. et al. 6,214,592 B1 4/2001 Crouzet et al. (21) Appl. No.: 12/813,469 6,274,790 B1 8/2001 Kunst et al. 6,280,986 B1 8/2001 Hespell et al. (22) Filed: Jun. 10, 2010 RE37,393 E 9/2001 Donnelly et al. (Continued) (65) Prior Publication Data US 2011/0008858 A1 Jan. 13, 2011 FOREIGN PATENT DOCUMENTS CN 1358 841 T 2002 EP O 494 O78 7, 1992 Related U.S. Application Data (Continued) (60) Provisional application No. 61/187,238, filed on Jun. OTHER PUBLICATIONS 15, 2009, provisional application No. 61/185.969, & 8 filed on Jun. 10, 2009. Allen, “Carboxylation of epoxides to beta-keto acids in cell extracts s of Xanthobacter strain Py2.” J. Bacteriol. (1996) 178(5): 1469-1472. 51) Int. C Abadjieva et al., “The Yeast ARG7 Gene Product is Autoproteolyzed (51) N i/20 (2006.01) to Two Subunit Peptides, Yielding Active Ornithine Acetyltransferase.” J. Biol. Chem. 275(15): 11361-11367 (2000). CI2N I/00 (2006.01) Abe et al., “Discovery of amide (peptide) bond synthetic activity in CI2N 9/00 (2006.01) Acyl-CoA synthetase.” J. Biol. Chem. 28.3(17): 11312-11321 (2008). CI2P 7/26 (2006.01) thatRisobutyrate Hsu, to Stil 3-hydroxyisobutyrate sts in Pseudomonasin . CE;of putida. CI2P 7/16 (2006.01) th Stereochemistry of -hydroxyisobutyrate dehydrogenase.” J. CI2P2/06 (2006.01) Chem. Soc. Perkin 16:1404-1406 (1979). C7H 2L/04 (2006.01) Abiko et al., “Localization of NAD-isocitrate dehydrogenase and (52) U.S. Cl. glutamate dehydrogenase in rice roots: candidates for providing car bon skeletons to NADH-glutamate synthase.” Plant Cell Physiol. USPC ........ 435/252.3; 435/243; 46:1724-1734 (2005). (58) Field of Classification Search .................. - - - - - None (Continued) See application file for complete search history. Primary Examiner — Anand Desai (56) Ref Cited Assistant Examiner — Iqbal H Chowdhury eerees e (74) Attorney, Agent, or Firm — Jones Day U.S. PATENT DOCUMENTS (57) ABSTRACT 3,513,209 A 5, 1970 Clement A non-naturally occurring microbial organism has at least one 3,912,586 A 10/1975 Kaneyuki et al. exogenous nucleic acid encoding a MEK pathway enzyme 3,965, 182 A 6, 1976 Worrel expressed in a sufficient amount to produce MEK. The MEK 4,048,196 A 9, 1977 Broecker et al. pathway includes an enzyme selected from an acetoacetyl 4,082,788 A 4, 1978 Mims 4,190.495 A 2f1980 Curtiss CoA dehydrogenase (bifunctional), an acetoacetyl-CoA 4,301,077 A 11, 1981 Pesa et al. aldehyde dehydrogenase, a 3-oxobutyraldehyde reductase, a 4,624,920 A 11, 1986 Inoue 3-oxobutanol dehydratase, an MEK oxidoreductase, a 3-ox 4,652,685 A 3, 1987 Cawse et al. obutyraldehyde aminotransferase, a 4-aminobutan-2-one 4,871,667 A 10, 1989 Imada et al. deaminase, a 2-amino-4-ketopentanoate (AKP) thiolase, an 5,079,143 A 1/1992 Klein et al. AKP aminotransferase, a 2,4-dioxopentanoate decarboxy 5,143,833. A 9, 1992 Datta lase, an AKP deaminase, an acetylacrylate decarboxylase, an 5,143,834 A 9, 1992 Glassner et al. 5,168,055 A 12/1992 Datta et al. AKP decarboxylase, a glutamate dehydrogenase, a 3-oxobu 5,173,429 A 12/1992 Gaddy et al. tyraldehyde oxidoreductase (aminating) and an AKP oxi 5, 182,199 A 1/1993 Hartley doreductase (aminating). A 2-butanol pathway further 5, 192,673 A 3, 1993 Jain et al. includes an MEK reductase. A method for producing MEKor 5,403,721 A 4, 1995 Ward, Jr. et al. 2-butanol includes culturing these organisms under condi 5,413,922 A 5/1995 Matsuyama et al. tions and for a sufficient period of time to produce MEK or 5,416,020 A 5, 1995 Severson et al. 2-butanol. 5,457,040 A 10/1995 Jarry et al. 5,478,952 A 12/1995 Schwartz 26 Claims, 4 Drawing Sheets US 8,420,375 B2 Page 2 U.S. PATENT DOCUMENTS 2007/0292927 A1 12/2007 Donaldson et al. 2008/O13887.0 A1 6/2008 Bramucci et al. S. R $383 syst al. 2008.0171371 A1 7, 2008 Yukawa et al. 6.432.686 B1 8/2002 Bulthuisetal 2008/0182308 A1 7/2008 Donaldson et al. 6.44806 Bi 9/2002 Panet al. 2008/0199926 A1 8/2008 Burgard et al. 6.455.284 B1 9, 2002 Gokarn et al 2008/0274522 A1 11/2008 Bramucci et al. 6,485,947 B1 11/2002 Rajgarhia etal 2008/0274525 A1 11/2008 Bramucci et al. 6,660,857 B3 2.2003 Agerbergeal 2008/0292927 A1 1 1/2008 Bramucci et al. 6,686.194 B1 2/2004 Mitzeletal 2008/0293125 A1 11/2008 Subbian et al. 6,686,310 Bi 2, 2004 Kouriakis etal 2009/0047718 A1 2/2009 Blaschek et al. 6,743,610 B2 6/2004 Donnellyet al. 2009/0047719 A1 2/2009 Burgard et al. 6.852.57 B1 2/2005 Suthersetal 2009 OO68207 A1 3, 2009 Breitbart et al. 7,127.379 B2 10/2006 Paisson et al. 2009.0075351 A1 3/2009 Burket al. 7.186541 B2 3/2007 Gokarnet al. 2009. O139134 A1 6/2009 Yashikuni et al. 7233,567 B2 5/2007 Ka Yiu et al. 2009/0305364 Al 12/2009 Burgard et al. 7.241594 B2 7/2007 fee etal 2010.0009419 A1 1/2010 Burk et al. 7244.610 B2 7/2007 Sanet al. 2010, 0021978 A1 1/2010 Burk et al. 7.256,016 B2 8/2007 Sanet al. 3888. A 388 Sialurk et al. 239, R: 658, Stil 2010. 0317069 A1 12/2010 Burk et al. 7.5875 357 E." 2010/0323418 A1 12/2010 Burgard 737.1558 B2 5/2008 Cervineral 2010/0330635 Al 12/2010 Burgard et al. 7.393.676 B2 7/2008 Gokarnet al 28:885. A 39 yetark et al. 2592, E: 1939 R et al. 2011/0014668 A1 1/2011 Osterhout et al. I - J. emakers-Franken et al. 2011/OO97767 A1 4, 2011 Ph. 7,569,380 B2 8, 2009 San et al. arkya 7,799.545 B2 9/2010 Burgardetal 2011/01298.99 A1 6, 2011 Haselbeck et al. 7,803.589 B2 9/2010 Burket al. 2011/O195461 A1 8/2011 Burk et al. 7.858,350 B2 12/2010 Burket al. 2011/0201068 A1 8/2011 Pharkya et al. 7947483 B2 5 2011 Burgard 2011/0201071 A1 8/2011 Burgard et al. 7977,084 B2 7/2011 Sunetal 2011/0207185 A1 8/2011 Osterhout 8,026,386 B2 92011 Burketal 2011/0207 189 A1 8/2011 Osterhout 8.048,661 B2 11/2011 Burgardeal 2011/0212507 A1 9/2011 Burgard et al. 8062.871 B2 1/2011 Burgardeal. 2011/0217742 A1 9, 2011 Sun et al. 8067.214 B2 ii/2011 Burke a 2011/0223637 A1 9, 2011 Burk et al. 8088.607 B2 1/2012 Burgardetal 2011/022994.6 A1 9, 2011 Haselbeck et al. 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