Biocatalysis @ DSM PDF
Preview Biocatalysis @ DSM
Biocatalysis @ DSM David Ager Principal Scientist DSM ChemTech R&D BV PMB 150 9650 Strickland Road, Suite 103 Raleigh NC 27615 USA [email protected] Biocatalysis AEAEllddnnoozzllaayysseemmssee PPllaattffoorrmmss APAPllccrroooohhddoolluuss,, ccDDiittoo llccss,,ll AAaammssiissnnooee aassccoohhoollss Num>> b13e7750r0000 00o00f eancczeysmsiebsle i nen DzySmMe es nfozry rmapei dc oslclreecetnioinng a t DSM PharmaPLE® Pseudomonas Candida sp. 1 HEMNNDOOHAAHALPHEMNNDOOHAAHALP>iiprprcmmcmmaiieyyaiieyyxmxmooppttttoorrrroo3yyddddlhlhiinnooaaiiiiimimddtteexxllllllaaddyyrrooeeeaeaaassaa0agagiioodndnaoaoddooaasslleessssccaahhxx ttrsrseexxeessnnsseeooeeoo--yyooyyyyeeesseeii TTsshhhhssddnniiaaaaggggssssnnrrooyyrrn nneeiieeaaaallttaaddllyynnddrrnnnnttssrrddziiaaaaaa ooaallsseeeeEEeessssssllssyaassaahheesseeeeeellmm,,ssaassyyttssssm sseeeeCCllaaiioo((rrnnss((ssaaPPggaaaaaaaeerree44ssllbbssssccnn55eeteeaaooaai00ssssmmhhss,,c eeooBBoo ssllaayy p&&eellaayy rssaaeeoeemmrr--ssVViic,,nn iiRRllooelliiaagg aascceecceerriis))mmdd))eaasssee ssimplemEEAACAAACAAAAAPEEAACAAACAAAAAPpplmepplmellmmmmmlllmmmmmlayayeccccccccoopoopaarrooiiooooooiiiiiiiiiibbddnxxxxnnttnnnnnnnnnnhhhhhhhhiiooiiiieeooddeooooeooooddoddoxxtoooooossshsheeleelee yyss,,ellllllaaaaaaaassssss ssssssyyll,,NNccccccccii ,,,,cc,,dd ,, ,,dSS a a iiiiiiiiiiDDDD AAEEddddddddAArrttaauunnrr iissssssssiiiissmmiinnllccllooooddllffddoee,,,,ttiioossllll dd eeiisssseessNNAAAAnnxxssnrrhhiieemm--ssmm,,dd yyAA ss,,NNee iiddiiicc,,CCddssnnii eettneeCCeeoorraassttiissaallrr yy,,deeaabb rrllCCssccbb--oouAAiiaaooxxddmmrrxxyysssbbyylliiiiootnneeccxxoorss aayyitt ccaaeellaiiiiccrrccddsslii ddssaa ssccsiiddcssale oooxxxiiidddoooNumber of enzymesNumber of enzymesrrreeeddd123456123456000000000000uuu00000000000000ccctttaaasssttteeerrraaasss11nnnsssCfffoeeerrrnaaatisssneeehhh22sssuyyyodddurrrooos lllaaaesssxeee33psssanlllsyyyiaaaosssneee44sss DBSCDBSCsssssssssuuuiiiiSoSouuuuuuogogddpppppppppMMcmcmeepppppppppaa axaxlllllllllttppiiiiiiiiiaaii--eeeeeeeeessllAAuullrrrrrrrrryy slsl dd333tt222111 iirrccppiiccssaahhrrttnneerrss McoMcoooffuu nnssttttaauuaattbbcciioouutt nnnnpp iiooaattssttiinntt Sporidiolobus >500 EnzTyhmermesoanaerobiumMoRrCaChxoaoernydlldnoaiecdobaca sccpute.s2rium Used in tons scale production Used in lab and pilot scale • Broadest collection of off the shelf enzymes (>3000) • Excellent expression and enzyme design capabilities • Secure supply of enzyme at any scale (with FTO!) • Unmet track record (also regulatory) in large scale implementation (>30 processes industrialized) • Critical mass for all important expertise • Open innovation approach provides access to huge network T226 V193 V194 D192 A199 G200 Enzyme classes split for industrial manufacturing DSM has access to all classes and has commercialized processes using all of the classes mentioned Straathof, A. J. J.; Panke, S.; Schmid, A. Curr. Opin. Biotechnol. 2002, 13, 548 DSM Enzyme Collection > 3000 enzymes ready for screening 100 90 80 70 60 50 40 30 20 10 0 Alcohol dehydrogenaEsneosate Pr4e5d0uctaseOsxidaSs-eosBmVegMRa--OosTLrm-aeAngsmai-anTmDori -anaAnacissmidae ntsrmoi ananacsisade Ttsmrriaannnasssaaesmmiinnaasseesss (eLtiso pt/ aalsP)eesp t/i dEastseers a/ seAsmidaAsemsiHdaalsoeaNlsitcriolhaEsopl eosdxiedhaalsDoe-gsHeyndaasnteL-soiHnyadsaenstoinase R-HaHlNAoLhmyS-dmriHonnNieLa ldyeahsalDeosegcearnbNaitosrxielyle ahsyedsratases a e ot Pr Industrial applications > 30 processes implemented Introduced Enzyme Platforms Product classes Aldolases Alcohols, Diols, Amino acohols 2005 Proteases Peptides, Amines, Carboxyesters Lipases and Esterases Alcohols, Esters, Carboxylic acids 2007 2008 Ammonia lyases Amino acids 2009 Hydantoinases, Carbamoylases, Racemases Amino acids Amidases Amino acids, Amides Acylases Amino acids, N-Acetyl-Amino acids Hydroxynitrile lyases Cyanohydrins 2009 Omega-Transaminases Amines Oxidases Alcohols, Aldehydes, Carboxylic acids 2010 Dehydrogenases (alcohol & amino acid) Alcohols and Amino acids Nitrilases Carboxylic acids, Nitriles Nitrile hydratases Amides, Nitriles Monooxygenases (P450, Baeyer-Villiger) Alcohols, Sulfoxides Epoxide hydrolases Epoxides, Diols Haloalcohol dehalogenases Epoxides, Diols Used in tons scale production Used in lab and pilot scale Enzymes used in large scale production Product Process Citric Acid Fermentation Vit. C Biotransformation: sorbitol à sorbose Vit. B2 Fermentation: Metabolic Engineering Aspartame Biocatalysis: Protease D-p-Hydroxyphenylglycine Biocatalysis: Hydantoinase / Carbamoylase 6-APA Fermentation & Biocatalysis: Acylase 7-ADCA Fermentation & Biocatalysis: Metabolic Engineering, Acylase Cephalexin Biocatalysis: Acylase Agro application Biocatalysis: Hydroxynitrile Lyase Commercial products ranging from 500 tpa to 100,000 tpa Expansion of Enzyme Spectrum Biodiversity through partnering DSM core competencies and in-house activities HTS cloning Enzyme in PluGbug production genes Application HTS screening (cGMP) & analysis P450s Regioselective hydroxylations, dealkylations Diverse enzymes: Diverse chemistry: CYP505B1 other self- sufficient > 50 CYP450s CYP102A1 (P450-BM3) CYP116B1 (P450-Rhf) Challenges in Applications of P450s Expression (membrane bound) Stability Challenges to be solved Selectivity/Activity Uncoupling √ scale-up NADH Regeneration + H+ RH + O 2 2 Pdx NAD+ R-OH + H O 2 PdR P450 Example: Bacterial three-component cytochrome P450 mono-oxygenases (PdR: putidaredoxin reductase; Pdx: putida-redoxin; P450: heme-containing monooxygenase). Classical and Targeted Pravastatin Process Bioconversion Secretion Glucose Streptomyces carbophilus Penicillium citrinum Compactin Pravastatin Glucose Pravastatin Penicillium chrysogenum Superior in terms of production costs and environment
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