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US010246727B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 246 ,727 B2 Zanghellini (45 ) Date of Patent: Apr . 2 , 2019 (54 ) FERMENTATION ROUTE FOR THE H05 137568 A 6 / 1993 PRODUCTION OF LEVULINIC ACID , H 05320023 A 12 / 1993 H 06280041 A 10 / 1994 LEVULINATE ESTERS AND H 09190820 A 7 / 1997 VALEROLACTONE AND DERIVATIVES 2009528842 A 8 / 2009 THEREOF WO WO 1995 /022524 AL 8 / 1995 WO WO 1998 / 043684 Al 10 / 1998 WO WO 2004 / 084633 A 10 / 2004 (71 ) Applicant : Arzeda Corp . , Seattle , WA (US ) WO WO 2004 /085048 A2 10 / 2004 WO WO 2004 /085349 A2 10 / 2004 ( 72 ) Inventor : Alexandre Luc Zanghellini, Seattle , wo WO 2004 /085390 A1 10 / 2004 WA (US ) WO WO 2005 / 028529 A2 3 / 2005 WO WO 2005 /063726 AL 7 / 2005 ( 73) Assignee : ARZEDA CORP. , Seattle , WA ( US) WO WO 2005 /097723 A2 10 / 2005 WO WO 2006 /015023 A2 2 / 2006 WO WO 2006 /015024 A1 2 / 2006 ( * ) Notice : Subject to any disclaimer , the term of this WO WO 2006 / 117113 A2 11 /2006 patent is extended or adjusted under 35 WO WO 2007 / 106524 A2 9 / 2007 U . S . C . 154 (b ) by 0 days . WO WO 2009 / 111513 AL 9 / 2009 WO WO 2009 / 142489 A2 11 / 2009 WO WO 2010 /051076 A1 5 / 2010 (21 ) Appl. No. : 15 / 347, 346 WO WO 2010 /065833 A2 6 / 2010 WO WO 2010 /077470 A2 7 / 2010 (22 ) Filed : Nov . 9 , 2016 WO WO 2011 / 066076 Al 6 / 2011 (65 ) Prior Publication Data WO WO 2012 /030860 Al 3 /2012 US 2017 /0275657 A1 Sep . 28 , 2017 OTHER PUBLICATIONS Alonso et al. , “ Catalytic conversion of biomass to biofuels .” Green Related U . S . Application Data Chemistry ( 2010 ) ; 12 ( 9 ) : 1493 - 1513 . (63 ) Continuation of application No . 13 /820 ,028 , filed as Blackwell , N . C ., “ Mechanistic and Structural Investigations of DOG Aldolase ," a thesis submitted for the degree of Doctor of application No. PCT/ US2011 /049788 on Aug . 30 , Philosophy at the University of Leicester, Oct. 2000 . 2011, now Pat . No . 9 , 523, 105 . Bozell, J . , " Connecting Biomass and petroleum processing with a chemical bridge ” , Science , 329 : 522 -523 (2010 ) . (60 ) Provisional application No . 61 /378 , 199 , filed on Aug . Bozell , J ., “ Production of levulinic acid and use as a platform 30 , 2010 . chemical for derived products ” , Resources , Conservation and Recy cling , 28 : 227 - 239 ( 2000 ) . (51 ) Int . CI. Bur et al. , “ An evaluation of the substrate specificity and asymmet C12P 7762 ( 2006 .01 ) ric synthesis potential of the cloned L - lactate dehydrogenase from C12P 7 /40 ( 2006 .01 ) Bacillus stearothermophi/ us , " Canadian Journal of Chemistry 67 : C12P 7 /42 ( 2006 .01 ) 1065 - 1070 ( 1989 ) . Causey , et al ., “ Engineering Escherichia coli for efficient conversion C12P 17 /04 ( 2006 .01 ) of glucose to pyruvate .” PNAS ( 2004 ) ; 101 ( 8 ) : 2235 - 2240 . (52 ) U . S . Ci. Extended European Search Report in European Patent Application CPC C12P 7762 ( 2013 .01 ) ; C12P 7 /40 (2013 . 01 ) ; No . EP 11822511. 9 dated Nov . 10 , 2016 , 10 pages . C12P 7742 ( 2013 . 01 ) ; C12P 17 / 04 ( 2013 .01 ) ; Evans, et al ., " C2- Symmetric Copper ( II ) Complexes as Chiral C12Y 101 /01 ( 2013 .01 ) ; C12Y 401/ 03016 Lewis Acids . Scope and Mechanism of the Catalytic Enantioselec tive Aldol Additions of Enolsilanes to Pyruvate Esters ” , J . Am . (2013 .01 ) ; C12Y 401/ 03039 (2013 .01 ); C12P Chem . Soc. , 121 : 686 -699 ( 1999 ) . 2203 /00 (2013 .01 ) ; YO2P 20 / 52 (2015 . 11 ) Ezeji, T . C . et al ., “ Bioproduction of butanol from biomass: from (58 ) Field of Classification Search genes to bioreactors” , Current Opinion in Biotechnology , 18 ( 3 ) : None 220 - 227 (2007 ) . Geary and Hultin , “ The state of the art in asymmetric induction : the See application file for complete search history . aldol reaction as a case study” , Tetrahedron : Asymmetry , 20 ( 2 ) : 131- 173 (2009 ) . ( 56 ) References Cited Ishiyama et al . , “ Structural studies of FlaAl from helicobacter pylori reveal the mechanism for inverting 4 , 6 -dehydratase activity ” , U . S . PATENT DOCUMENTS J . Bio . Chem ., 281 ( 34 ) : 24489 - 24495 ( 2006 ) . 5 ,769 , 929 A 6 / 1998 Gundlach et al . (Continued ) 6 , 965, 058 B1 11 / 2005 Raidel et al. 7 , 153 , 996 B2 12 / 2006 Fagan Primary Examiner — Sharmila G Landau 9 , 523 , 105 B2 12 / 2016 Zanghellini 2008 /0242721 A1 10 / 2008 Selifonov Assistant Examiner — Stephen M Chong 2009 /0191607 A1 7 / 2009 Baker et al. (74 ) Attorney, Agent, or Firm — Cooley LLP 12 / 2013 Zanghellini 2013/ 0330779 Al ( 57 ) ABSTRACT FOREIGN PATENT DOCUMENTS The invention provides processes for the conversion of pyruvate obtained from sugars or other carbon sources , to CN 1643116 A 7 /2005 EP 0496555 A2 7 / 1992 valuable C5 materials such as levulinic acid , levulinate EP 0882745 Al 12 / 1998 esters , valerolactone , and derivatives thereof. EP 1533364 A2 5 /2005 EP 1716131 B1 11 / 2006 6 Claims, 9 Drawing Sheets US 10 ,246 ,727 B2 Page 2 ( 56 ) References Cited PCT/ US2011 / 049788 , International Preliminary Report on Patent ability , dated Mar. 5 , 2013 , 5 pages . Pollard , J . R . et al ., " Substrate selectivity and biochemical proper OTHER PUBLICATIONS ties of 4 -hydroxy - 2 -keto - pentanoic acid aldolase from Escherichia Li, Y ., et al ., “ Biotechnological production of pyruvic acid ” , Applied coli” , Applied and Environmental Microbiology , 64 ( 10 ) : 4093 -4094 Microbiology and Biotechnology , 57 : 451 -459 ( 2001 ) . ( 1998 ) . Lüönd , R . M . , et al ., “ Assessment of the active -site requirements of Serrano -Ruiz et al . , “ Catalytic upgrading of levulinic acid to 5 - aminolaevulinic acid dehydratase : Evaluation of substrate and 5 - nonanone" , Green Chemistry , 12 ( 4 ) : 574 -577 ( 2010 ) . product analogues as competitive inhibitors ” , J . Org . Chem . , 57 ( 18 ): Stuermer et al ., “ Asymmetric bioreduction of activated C = C bonds 5005 - 5013 ( 1992 ) . using enoate reductases from the old yellow enzyme family ” , Martin , C . H . , et al. , “ Integrated bioprocessing for pH -dependent of Current Opinion in Chemical Biology , 11 ( 2 ) : 203 - 213 (2007 ) . 4 - valerolactone from levulinate in Pseudomonas Putida KT2440 " , Appl. and Environ , Microbiology , 76 ( 2 ) : 417 -424 (2010 ) . Wang, W . , et al ., “ Comparison of two metal- dependent pyruvate Martin , C . H . et al. , “ High -titer production ofmonomeric hydroxyvaler aldolases related by convergent evolution : substrate specificity , ates from levulinic acid in Pseudomonas putida ” , Journal of Bio kinetic mechanism , and substrate channeling ” , Biochemistry , 49 : technology , 139 ( 1 ) : 61 -67 (2009 ) . 3774 - 3782 ( 2010 ) . Meyers et al . , “ Stereoselective alkylations in rigid systems. Effect of Wang and Seah , “ Purification and biochemical characterization of a remote substituents on p - facial additions to lactam enolates . pyruvate- specific Class II aldolase, Hpal ” , Biochemistry , 44 ( 27 ) : Stereoelectronic and steric effects ” , J . Am . Chem . Soc. , 120 ( 30 ) : 9447 - 9455 ( 2005 ) . 7429 - 7438 ( 1998 ) . Zanghellini, A . et al ., “ New algorithms and an in silico benchmark PCT/ US2011 / 049788 , International Search Report and Written Opin for computational enzyme design ” , Protein Science, 15 ( 12 ) : 2785 ion , dated Jan . 19 , 2012 , 10 pages . 2794 ( 2006 ) . atent Apr. 2 , 2019 Sheet 1 of 9 US 10 ,246 ,727 B2 2-cidroxiperamoiosad substituidowaerersa 50 :*10 ** OXO,2-yarmypantanoirand PA FIG.I atent Apr. 2 , 2019 Sheet 2 of 9 US 10 ,246 ,727 B2 atent Apr. 2 , 2019 Sheet 3 of 9 US 10 ,246 ,727 B2 FIG . 3 . C6 sugars (glucose ) . CS sug?rs mimo www . Lipid metabolism . - . 2NAOH . SZSÁJOOKS . : 2NADH . - . decarboxylation : . ( pyruvate decarboxylase, . aldoi addition . { 8 !dolase ) . NAOH . reduction . EDELS. (dehydrogenase ) . 2. NADH COS oxidation . HOVN ) aseuabookuso{ . 23 derydration . (dehydratase . 4 -valerolacione . FMNH2 NAOH : 9d3lS ee... ZHNW prosta reduction lacionization e ( enoate reductase ) STER ? (lactonase ) v NAO NADH NAOH (dehydrogenaseexcluation ) atent Apr. 2 , 2019 Sheet 4 of 9 US 10 ,246 ,727 B2 FIG . 4 C6 sugars ( glucose ) C5 sugars - - - Lipid metabolism glycolysis 2NAD + 2NADH ??arbaxytation 002 (pyruvate decarboxylase ) aldol addition ( aldolase ) ( NAD oxidation NADH (dehydrogenase ) NADH OM reduction NADH (dehydrogenase ) OH STEPS dehydration (dehydratase ) 4 -valerolactone FMNH2 ?? NADH reduction FMNH2 STEP 7 lactonization NAD + (enoate reductase } (lactonase NADH NAD + OH reduction(dehydrogenase ) atent Apr. 2 , 2019 Sheet 5 of 9 US 10 ,246 ,727 B2 FIG . 5 * . decarboxylation . idol addition . oxidative dersydration valecolactone . :. .. atent Apr. 2 , 2019 Sheet 6 of 9 US 10 ,246 ,727 B2 FIG . 6 C6 sugars (glucose ) C5 sugars im Lipid metabolism glycolysis 2NAD + 2NADH . pyruvate decarboxylase. CO2 . : : : : : : : . other . .. .. .. .. OH . aldolase . COA synthase . hydrolysis . NADA . SCOA NADH lactonization . NAOH . dehydrogenase dehydrogenase . ' ' ' ' ' ' ' ' ' ' ' . .. .. .. .. * dehydrogenase NAD + . NAD + NAD + . OH OH COA synthase OH : hydrolysis . NAD + SCOA thioesterase NAD + OH lactonization dehydrogenase dehydrogenase OH . .. NADH dehydratase NADH . CoA synthase . OH . SCOA thioesterase reductase dehydratase dehydratase CoA synthase g - valerolactone FMNH2 SCOA FMNH2 NADH : thloesterase NADH reductase reductase FMNH2 . FMNH2 . NAD lactonization NAD + . COA synthase . NADA NAD + . thioesterase . dehydrogenase . SCOA OH . U. S . Patent atent Apr. 2 , 2019 Sheet 7 of 9 US 10 ,246 ,727 B2 ANA COAsynthase thioesterase SCOA . : . transferase O-R .. .. HOR withR-El,MetAryl. FIG.7 atent Apr. 2 , 2019
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    Supplementary Informations SI2. Supplementary Table 1. M9, soil, and rhizosphere media composition. LB in Compound Name Exchange Reaction LB in soil LBin M9 rhizosphere H2O EX_cpd00001_e0 -15 -15 -10 O2 EX_cpd00007_e0 -15 -15 -10 Phosphate EX_cpd00009_e0 -15 -15 -10 CO2 EX_cpd00011_e0 -15 -15 0 Ammonia EX_cpd00013_e0 -7.5 -7.5 -10 L-glutamate EX_cpd00023_e0 0 -0.0283302 0 D-glucose EX_cpd00027_e0 -0.61972444 -0.04098397 0 Mn2 EX_cpd00030_e0 -15 -15 -10 Glycine EX_cpd00033_e0 -0.0068175 -0.00693094 0 Zn2 EX_cpd00034_e0 -15 -15 -10 L-alanine EX_cpd00035_e0 -0.02780553 -0.00823049 0 Succinate EX_cpd00036_e0 -0.0056245 -0.12240603 0 L-lysine EX_cpd00039_e0 0 -10 0 L-aspartate EX_cpd00041_e0 0 -0.03205557 0 Sulfate EX_cpd00048_e0 -15 -15 -10 L-arginine EX_cpd00051_e0 -0.0068175 -0.00948672 0 L-serine EX_cpd00054_e0 0 -0.01004986 0 Cu2+ EX_cpd00058_e0 -15 -15 -10 Ca2+ EX_cpd00063_e0 -15 -100 -10 L-ornithine EX_cpd00064_e0 -0.0068175 -0.00831712 0 H+ EX_cpd00067_e0 -15 -15 -10 L-tyrosine EX_cpd00069_e0 -0.0068175 -0.00233919 0 Sucrose EX_cpd00076_e0 0 -0.02049199 0 L-cysteine EX_cpd00084_e0 -0.0068175 0 0 Cl- EX_cpd00099_e0 -15 -15 -10 Glycerol EX_cpd00100_e0 0 0 -10 Biotin EX_cpd00104_e0 -15 -15 0 D-ribose EX_cpd00105_e0 -0.01862144 0 0 L-leucine EX_cpd00107_e0 -0.03596182 -0.00303228 0 D-galactose EX_cpd00108_e0 -0.25290619 -0.18317325 0 L-histidine EX_cpd00119_e0 -0.0068175 -0.00506825 0 L-proline EX_cpd00129_e0 -0.01102953 0 0 L-malate EX_cpd00130_e0 -0.03649016 -0.79413596 0 D-mannose EX_cpd00138_e0 -0.2540567 -0.05436649 0 Co2 EX_cpd00149_e0
  • Functional and Physiological Discovery in the Mannonate Dehydratase Subgroup of the Enolase Superfamily

    Functional and Physiological Discovery in the Mannonate Dehydratase Subgroup of the Enolase Superfamily

    FUNCTIONAL AND PHYSIOLOGICAL DISCOVERY IN THE MANNONATE DEHYDRATASE SUBGROUP OF THE ENOLASE SUPERFAMILY BY DANIEL JOSEPH WICHELECKI DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biochemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2014 Urbana, Illinois Doctoral Committee: Professor John Gerlt, Chair Professor John Cronan Professor Scott Silverman Professor Wilfred van der Donk ABSTRACT In the current post-genomic world, the exponential amassing of protein sequences is overwhelming the scientific community’s ability to experimentally assign each protein’s function. The use of automated, homology-based annotations has allowed a reprieve from this efflux of data, but has led to widespread misannotation and nonannotation in protein sequence databases. This dissertation details the functional and physiological characterization of the mannonate dehydratase subgroup (ManD) of the enolase superfamily (ENS). The outcome affirms the dangers of homology-based annotations while discovering novel metabolic pathways. Furthermore, the experimental verification of these pathways ( in vitro and in vivo ) has provided a platform to test the general strategies for improved functional and metabolic characterization being developed by the Enzyme Function Initiative (EFI). Prior to this study, one member of the ManD subgroup had been characterized and was shown to dehydrate D-mannonate to 2-keto-3-deoxy-D-gluconate. Forty-two additional members of the ManD, selected from across the sequence space of the subgroup, were screened for activity and kinetic constants were determined. The members of the once isofunctional subgroup were found to differ in both catalytic efficiency and substrate specificity: 1) high 3 4 -1 -1 efficiency (k cat /K M = 10 to 10 M s ) dehydration of D-mannonate, 2) low efficiency (k cat /K M = 10 1 to 10 2 M-1s-1) dehydration of D-mannonate and/or D-gluconate, and 3) no-activity with either D-mannonate or D-gluconate (or any other acid sugar tested).
  • Extracting Chemical Reactions from Biological Literature

    Extracting Chemical Reactions from Biological Literature

    Extracting Chemical Reactions from Biological Literature Jeffrey Tsui Electrical Engineering and Computer Sciences University of California at Berkeley Technical Report No. UCB/EECS-2014-109 http://www.eecs.berkeley.edu/Pubs/TechRpts/2014/EECS-2014-109.html May 16, 2014 Copyright © 2014, by the author(s). All rights reserved. Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. To copy otherwise, to republish, to post on servers or to redistribute to lists, requires prior specific permission. Extracting Chemical Reactions from Biological Literature Jeffrey Tsui Master of Science in Computer Science University of California, Berkeley Advisor: Ras Bodik Abstract Table of Contents Synthetic biologists must comb through vast amounts of 1. Introduction academic literature to design biological systems. The 2. Related Works majority of this data is unstructured and difficult to query 3. Extracting Reactions using Patterns because they are manually annotated. Existing databases 3.1 Pattern Representation such as PubMed already contain over 20 million citations 3.2 Extraction Process and are growing at a rate of 500,000 new citations every 3.2 Sentence Parsing year. Our solution is to automatically extract chemical 4. Creating a Training Set reactions from biological text and canonicalize them so that they can be easily indexed and queried. This paper 4.1 Reaction Labeling describes a natural language processing system that 4.2 Assumptions and Limitations generates patterns from labeled training data and uses them 5.