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United States Patent (10 ) Patent No.: US 10,501,760 B2 Kumaran Et Al

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United States Patent (10 ) Patent No.: US 10,501,760 B2 Kumaran Et Al US010501760B2 United States Patent (10 ) Patent No.: US 10,501,760 B2 Kumaran et al. (45 ) Date of Patent : Dec. 10 , 2019 ( 54 ) METHODS FOR PRODUCTION OF (56 ) References Cited OXYGENATED TERPENES U.S. PATENT DOCUMENTS ( 71) Applicants :GIVAUDAN SA , Vernier ( CH ) ; 5,847,226 A * 12/1998 Muller C07C 29/50 MANUS BIOSYNTHESIS , INC . , 568/346 Cambridge, MA (US ) 6,200,786 B1 3/2001 Huang et al . 6,890,960 B1 5/2005 Henderson et al. 7,211,420 B1 5/2007 Wong et al . ( 72 ) Inventors : Ajikumar Parayil Kumaran , 7,273,735 B2 9/2007 Schalk et al . Cambridge , MA (US ) ; Chin Giaw Lim , 8,097,442 B2 1/2012 Hitchman et al . Allston , MA (US ) ; Liwei Li, Arlington , 8,415,136 B1 4/2013 Gardner et al. 8,512,988 B2 8/2013 Ajikumar et al. MA (US ) ; Souvik Ghosh , Cambridge , 8,927,241 B2 1/2015 Ajikumar et al. MA (US ) ; Christopher Pirie , 9,284,570 B2 3/2016 Stephanopoulos et al. Cambridge, MA (US ) ; Anthony 9,359,624 B2 6/2016 Ajikumar et al. Qualley , Beavercreek , OH (US ) ; Geoff 9,494,130 B2 8/2016 Ajikumar et al . 9,796,980 B2 10/2017 Ajikumar et al . Marshall -Hill , Buckinghamshire (GB ) ; 9,957,527 B2 5/2018 Ajikumar et al . Martin Preininger , Neuss (DE ) 2011/0189717 Al 8/2011 Ajikumar et al. 2012/0107893 Al 5/2012 Ajikumar et al. ( 73 ) Assignees : GIVAUDAN SA , Vernier ( CH ) ; 2012/0164678 A1 6/2012 Stephanopoulos et al . MANUS BIOSYNTHESIS , INC ., 2012/0246767 Al 9/2012 Amick et al . 2017/0002366 A1 1/2017 Ajikumar et al . Cambridge , MA (US ) 2017/0002382 A1 1/2017 Ajikumar et al . 2017/0332673 A1 11/2017 Philippe et al . ( * ) Notice : Subject to any disclaimer, the term of this 2018/0135081 Al 5/2018 Kumaran et al . patent is extended or adjusted under 35 2018/0251738 A1 9/2018 Donald et al. U.S.C. 154 ( b ) by 0 days . FOREIGN PATENT DOCUMENTS ( 21 ) Appl. No.: 15 /505,022 JP 2004-067723 3/2004 WO 2006/079020 7/2006 (22 ) PCT Filed : Aug. 21 , 2015 WO 2011060057 5/2011 WO 2016029187 2/2016 ( 86 ) PCT No .: PCT /US2015 /046421 § 371 (c ) (1 ), OTHER PUBLICATIONS (2 ) Date : Feb. 17 , 2017 Unknown author, title : Beta -nootkaton , product information from PCT Pub . No .: WO2016 /029187 Pubchem , downloaded from https://pubchem.ncbi.nlm.nih.gov/ ( 87 ) compound /Nootkatol . ( Year: 2018 ) . * PCT Pub . Date: Feb. 25 , 2016 Database WPI , Week 200423 , Thomson Scientific , London , GB : AN 2004-244290 , XP002752397, & JP 2004 067723 ( Hasegawa Co (65 ) Prior Publication Data Ltd.) Mar. 4 , 2004 . Database GENPEPT, “ Predicted : ent- kaurene oxidase , chloroplastic US 2018/0327789 A1 Nov. 15 , 2018 like (Malus domestica ], ” XP002752377, Jun . 20 , 2014 . Humphrey , T.V. et al. , “ Spatial organisation of four enzymes from Stevia rebaudiana that are involved in steviol glycoside synthesis ," Related U.S. Application Data Plant Molecular Biology ( 2006 ) 61: 47-62 . Schuckel, J. et al ., “ A Gene - Fusion Approach to Enabling Plant (60 ) Provisional application No. 62/ 040,284 , filed on Aug. Cytochromes P450 for Biocatalysis ,” Chembiochem , vol. 13 , No. 21, 2014 . 18 , Nov. 5 , 2012 , pp . 2758-2763 . Seifert , A. et al. , “ Rational Design of a Minimal and Highly (51 ) Int. Ci. Enriched CYP102A1 Mutant Library with Improved Regio- , Ste C12P 7/26 ( 2006.01 ) reo- and Chemoselectivity ,” Chembiochem , vol . 10 , No. 5 , Mar. 23 , C12N 9/02 ( 2006.01 ) 2009 . AOIN 27/00 ( 2006.01) (Continued ) C12P 5/00 ( 2006.01 ) A23L 27/12 (2016.01 ) Primary Examiner Yanzhi Zhang (52 ) U.S. CI. (74 ) Attorney, Agent, or Firm Stoel Rives LLP CPC C12P 7/26 (2013.01 ) ; A01N 27/00 (57 ) ABSTRACT ( 2013.01) ; A23L 27/13 ( 2016.08 ) ; C12N 9/0073 (2013.01 ) ; C12P 5/002 (2013.01 ) ; The present disclosure relates to methods for producing C12Y 114/13078 (2013.01 ) ; A23V 2002/00 oxygenated terpenoids, and preparation of compositions and ( 2013.01 ) ; CO7K 2319/03 (2013.01 ) formulations thereof . Polynucleotides, derivative enzymes , (58 ) Field of Classification Search and host cells for use in such methods are also provided . CPC C12P 7/26 ; C12Y 114/13078 ; A23L 27/13 ; A23V 2002/00 13 Claims, 76 Drawing Sheets See application file for complete search history . Specification includes a Sequence Listing . US 10,501,760 B2 Page 2 ( 56 ) References Cited Kumaran , et al. , Office Action dated Mar. 19 , 2019 for U.S. Appl. No. 15 / 505,503 . Kumaran , et al ., Preliminary Amendment dated Sep. 26 , 2017 for OTHER PUBLICATIONS U.S. Appl . No. 15 / 505,503 . UNIPROT Database , Humphrey , T.V. et al ., “ Subname: Full = Ent Kumaran , et al. , Restriction Requirement dated Dec. 20 , 2018 for kaurene oxidase CYP701A5 , " Feb. 19 , 2014 . U.S. Appl. No. 15 / 505,503 . UNIPROT Database , Humphrey, T.V. et al. , “ Subname: Full = International Search Report and Written Opinion for International kaurene oxidase , ” Jul. 9 , 2014 . application PCT/ US2016 /047692 . Wriessnegger et al ., “ Production of the sesquiterpenoid ( + ) Ajikumar , et al. , “ Isoprenoid Pathway Optimization for Taxol nootkatone by metabolic engineering of Pichia pastoris, ” Metabolic Precursor Overproduction in Escherichia coli” , Science , 2010 , vol . Engineering, vol. 24 , Apr. 16 , 2014, pp . 18-29 . 1 , No. 330 (6000 ), pp . 1-11. International Search Report and Written Opinion dated Mar. 22 , Chang , et al ., “ Engineering Escherichia coli for Production of 2016 as received in PCT /US2015 / 046421. International Search Report and Written Opinion dated Dec. 14 , Functionalized Terpenoids Using Plant P450s” , Nature , 2007 , Chemi 2015 for international application PCT /US2015 / 046369 . cal Biology , vol. 3 , No. 5 , pp . 274-277 . Drew , et al. , Transcritome Analysis of Thapsia laciniata Rouy Pro Lange, et al. , “ Isoprenoid Biosynthesis : The Evolution of Two vides Insights into Terpenoid Biosynthesis and Diversity in Apiaceae, Ancient and Distinct Pathways Across Genomes ” , PNAS 97 : 13172 2013 International Journal ofMolecular Sciences, 2013 , vol. 14 , pp . 13177 , 2000 ( Year 2000 ) . 9080-9098 . Leonard , et al. , “ Functional Expression of a P450 Flavonoid Hydroxy Hotze , et al. ,Cinnamate 4 -hydroxylase from Catharanthus Roseuseand Lase for the Biosynthesis of Plant- Specific Hydroxlated Flavonols and Strategy for the Functional Expression of Plant Cytochrome in Escherichia Coli” , Metabolic Engineering , 2007 , vol. 8 , pp . P.450 Proteins as Translational Fusions with P450 Reductase in 172-181 . Escherichia coli, FEBS Letters , 1995 , vol. 374 , pp . 345-350 . Singh , “ Chemistry of Terpenoids and Carotenoids” , Discovery King , et al. , Production of Bioactive Diterpenoids in the Euphorbiaceae Publishing House , New Delhi , 2007 , pp . 3 and 4 ( Year : 2007) . Depends on Evolutionary Conserved Gene Clusters , The Plant Cell, 2014 , vol. 26 , pp . 3286-3298 . * cited by examiner U.S. Patent Dec. 10 , 2019 Sheet 1 of 76 US 10,501,760 B2 ??? ? - ??????? ????????????????????- FIG.1 4444: U.S. Patent Dec. 10 , 2019 Sheet 2 of 76 US 10,501,760 B2 1.5-2 1.2-1.5 FoldProductivityrelative(toWT) 0.8-1.2 FIG.2 0.5-0.8 0.2-0.5 140 120 100 80 09 40 20 0 No. of Mutants U.S. Patent Dec. 10 , 2019 Sheet 3 of 76 US 10,501,760 B2 > VvVS ( Vitis vinifera ] MSTQVSASSLAQIPQPKNRPVANFHPNIWGDQFITYTPEDKVTRACKEEQIEDLKKEV KRKLTAAAVANPSOLLNFIDAVORLGVAYHFEQEIEEALQHICNSFHDCNDMDGDLYN IALGFRLLRQQGYTISCDIFNKFTDERGRFKEALISDVRGMLGLYEAAHLRVHGEDIL AKALAFTTTHLKAMVESLGYHLAEQVAHALNRPIRKGLERLEARWYISVYQDEAFHDK TLLELAKLDFNLVOSLHKEELSNLARWWKELDFATKLPFARDRLVEGYFWMHGVYFEP QYLRGRRILTKVIAMTSILDDIHDAYGTPEELKLFIEAIERWDINSINOLPEYMKLCY VALLDVYKEIEEEMEKEGNQYRVHYAKEVMKNQVRAYFAEAKWLHEEHVPAFEEYMRV ALASSGYCLLATTSFVGMGEIATKEAFDWVTSDPKIMSSSNFITRLMDDIKSHKFEOK RGHVTSAVECYMKQYGVSEEQVYSEFQKQIENAWLDINQECLKPTAVSMPLLARLLNF TRTMDVIYKEQDSYTHVGKVMRDNIASVFINAVI ( SEQ ID NO : 1 ) ATGGCTACGCAGGTCTCAGCCTCGTCACTGGCACAAATCCCGCAGCCGAAAAATCGTC CGGTGGCGAACTTCCATCCGAATATCTGGGGTGACCAGTTTATCACGTATACCCCGGA AGATAAAGTGACCCGTGCGTGCAAGGAAGAACAAATTGAAGACCTGAAAAAGGAAGTC AAACGCAAGCTGACCGCAGCAGCAGTGGCAAACCCGTCTCAGCTGCTGAATTTTATCG ATGCGGTTCAACGTCTGGGCGTCGCCTATCATTTCGAACAGGAAATTGAAGAAGCACT GCAACATATCTGCAACAGCTTTCACGATTGTAATGATATGGACGGCGATCTGTATAAC ATTGCTCTGGGTTTCCGTCTGCTGCGCCAGCAAGGCTACACGATTTCCTGTGACATCT TTAATAAATTCACCGATGAACGTGGTCGCTTTAAGGAAGCGCTGATCTCAGACGTTCG TGGCATGCTGGGTCTGTATGAAGCTGCGCATCTGCGCGTCCACGGCGAAGATATTCTG GCCAAAGCACTGGCTTTCACCACGACCCACCTGAAGGCGATGGTCGAATCTCTGGGTT ACCATCTGGCAGAACAGGTGGCACACGCCCTGAACCGTCCGATCCGCAAAGGCCTGGA ACGTCTGGAAGCGCGCTGGTATATTAGTGTGTACCAGGACGAAGCATTTCATGATAAA ACCCTGCTGGAACTGGCTAAGCTGGATTTCAACCTGGTTCAATCTCTGCACAAAGAAG AACTGAGTAATCTGGCCCGTTGGTGGAAAGAACTGGACTTTGCGACCAAGCTGCCGTT CGCCCGTGATCGCCTGGTTGAAGGCTATTTTTGGATGCATGGTGTCTATTTCGAACCG CAGTACCTGCGCGGTCGTCGCATTCTGACGAAAGTGATCGCAATGACCTCGATTCTGG ATGACATCCACGACGCTTACGGCACCCCGGAAGAACTGAAACTGTTTATTGAAGCGAT CGAACGTTGGGATATTAACAGCATCAATCAGCTGCCGGAATATATGAAACTGTGCTAC GTGGCCCTGCTGGATGTTTACAAGGAAATCGAAGAAGAAATGGAAAAGGAAGGTAACC AGTATCGTGTTCATTACGCGAAAGAAGTCATGAAGAATCAAGTGCGCGCCTACTTTGC AGAAGCTAAATGGCTGCATGAAGAACACGTGCCGGCGTTCGAAGAATATATGCGCGTT GCGCTGGCCAGCTCTGGCTACTGTCTGCTGGCCACGACCTCTTTTGTGGGCATGGGTG AAATTGCAACGAAAGAAGCGTTTGACTGGGTTACCAGTGATCCGAAGATTATGAGTTC CTCAAACTITATCACCCGTCTGATGGATGACATTAAATCCCATAAGTTCGAACAGAAA CGCGGTCACGTCACCTCAGCCGTGGAATGCTATATGAAACAGTACGGCGTTTCGGAAG AACAAGTCTATAGCGAATTTCAGAAACAAATCGAAAACGCATGGCTGGATATTAATCA GGAATGTCTGAAACCGACGGCAGTCTCCATGCCGCTGCTGGCTCGTCTGCTGAATTTT ACGCGCACGATGGATGTGATCTATAAAGAACAGGATTCGTACACCCATGTGGGCAAGG TTATGCGCGATAACATTGCAAGCGTGTTCATTAATGCTGTTATCTAA ( SEQ ID NO : 2 ) FIG . 3A U.S. Patent Dec. 10 , 2019 Sheet 4 of 76 US 10,501,760 B2 > Vv1M1 | engineered valencene synthase MATOVSASSLAQIPQPKNRPVANFHPNIWGDQFITYTPEDKVTRACKEEQIEDLKKEV
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