Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.
Identifieur interne : 000871 ( Main/Exploration ); précédent : 000870; suivant : 000872Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.
Auteurs : Aleksandra Wlodek [Royaume-Uni] ; Steve G. Kendrew [Royaume-Uni] ; Nigel J. Coates [Royaume-Uni] ; Adam Hold [Royaume-Uni] ; Joanna Pogwizd [Royaume-Uni] ; Steven Rudder [Royaume-Uni] ; Lesley S. Sheehan [Royaume-Uni] ; Sarah J. Higginbotham [Royaume-Uni] ; Anna E. Stanley-Smith [Royaume-Uni] ; Tony Warneck [Royaume-Uni] ; Mohammad Nur-E-Alam [Royaume-Uni, Arabie saoudite] ; Markus Radzom [Royaume-Uni, Allemagne] ; Christine J. Martin [Royaume-Uni] ; Lois Overvoorde [Royaume-Uni] ; Markiyan Samborskyy [Royaume-Uni] ; Silke Alt [Royaume-Uni] ; Daniel Heine [Royaume-Uni] ; Guy T. Carter [États-Unis] ; Edmund I. Graziani [États-Unis] ; Frank E. Koehn [États-Unis] ; Leonard Mcdonald [États-Unis] ; Alexander Alanine [Suisse] ; Rosa María Rodríguez Sarmiento [Suisse] ; Suzan Keen Chao [Suisse] ; Hasane Ratni [Suisse] ; Lucinda Steward [Suisse] ; Isobel H. Norville [Royaume-Uni] ; Mitali Sarkar-Tyson [Royaume-Uni, Australie] ; Steven J. Moss [Royaume-Uni] ; Peter F. Leadlay [Royaume-Uni] ; Barrie Wilkinson [Royaume-Uni] ; Matthew A. Gregory [Royaume-Uni]Source :
- Nature communications [ 2041-1723 ] ; 2017.
Descripteurs français
- KwdFr :
- MESH :
- composition chimique : Sirolimus.
- génétique : Polyketide synthases, Voies de biosynthèse.
- métabolisme : Sirolimus.
- Bioingénierie, Famille multigénique, Variation génétique, Évolution moléculaire.
English descriptors
- KwdEn :
- MESH :
- chemical , chemistry : Sirolimus.
- chemical , genetics : Polyketide Synthases.
- genetics : Biosynthetic Pathways.
- chemical , metabolism : Sirolimus.
- Bioengineering, Evolution, Molecular, Genetic Variation, Multigene Family.
Abstract
Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.
DOI: 10.1038/s41467-017-01344-3
PubMed: 29089518
PubMed Central: PMC5663706
Affiliations:
- Allemagne, Arabie saoudite, Australie, Royaume-Uni, Suisse, États-Unis
- Angleterre, Angleterre de l'Est
- Cambridge
- Université de Cambridge
Links toward previous steps (curation, corpus...)
Le document en format XML
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Carter</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Graziani, Edmund I" sort="Graziani, Edmund I" uniqKey="Graziani E" first="Edmund I" last="Graziani">Edmund I. Graziani</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Medicine Discovery Network-Synthetic Biology, Pfizer Worldwide R&D, 445 Eastern Point Rd., Groton, CT, 06340, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medicine Discovery Network-Synthetic Biology, Pfizer Worldwide R&D, 445 Eastern Point Rd., Groton, CT, 06340</wicri:regionArea><wicri:noRegion>06340</wicri:noRegion></affiliation></author><author><name sortKey="Koehn, Frank E" sort="Koehn, Frank E" uniqKey="Koehn F" first="Frank E" last="Koehn">Frank E. Koehn</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Mcdonald, Leonard" sort="Mcdonald, Leonard" uniqKey="Mcdonald L" first="Leonard" last="Mcdonald">Leonard Mcdonald</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Alanine, Alexander" sort="Alanine, Alexander" uniqKey="Alanine A" first="Alexander" last="Alanine">Alexander Alanine</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Rodriguez Sarmiento, Rosa Maria" sort="Rodriguez Sarmiento, Rosa Maria" uniqKey="Rodriguez Sarmiento R" first="Rosa María" last="Rodríguez Sarmiento">Rosa María Rodríguez Sarmiento</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Chao, Suzan Keen" sort="Chao, Suzan Keen" uniqKey="Chao S" first="Suzan Keen" last="Chao">Suzan Keen Chao</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Ratni, Hasane" sort="Ratni, Hasane" uniqKey="Ratni H" first="Hasane" last="Ratni">Hasane Ratni</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Steward, Lucinda" sort="Steward, Lucinda" uniqKey="Steward L" first="Lucinda" last="Steward">Lucinda Steward</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Norville, Isobel H" sort="Norville, Isobel H" uniqKey="Norville I" first="Isobel H" last="Norville">Isobel H. Norville</name><affiliation wicri:level="1"><nlm:affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Defence Science and Technology Laboratory, Porton Down, PO17 6AD</wicri:regionArea><wicri:noRegion>PO17 6AD</wicri:noRegion></affiliation></author><author><name sortKey="Sarkar Tyson, Mitali" sort="Sarkar Tyson, Mitali" uniqKey="Sarkar Tyson M" first="Mitali" last="Sarkar-Tyson">Mitali Sarkar-Tyson</name><affiliation wicri:level="1"><nlm:affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Defence Science and Technology Laboratory, Porton Down, PO17 6AD</wicri:regionArea><wicri:noRegion>PO17 6AD</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Monash Avenue, Nedlands, WA, 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Monash Avenue, Nedlands, WA, 6009</wicri:regionArea><wicri:noRegion>6009</wicri:noRegion></affiliation></author><author><name sortKey="Moss, Steven J" sort="Moss, Steven J" uniqKey="Moss S" first="Steven J" last="Moss">Steven J. Moss</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Leadlay, Peter F" sort="Leadlay, Peter F" uniqKey="Leadlay P" first="Peter F" last="Leadlay">Peter F. Leadlay</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wilkinson, Barrie" sort="Wilkinson, Barrie" uniqKey="Wilkinson B" first="Barrie" last="Wilkinson">Barrie Wilkinson</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH</wicri:regionArea><wicri:noRegion>NR4 7UH</wicri:noRegion></affiliation></author><author><name sortKey="Gregory, Matthew A" sort="Gregory, Matthew A" uniqKey="Gregory M" first="Matthew A" last="Gregory">Matthew A. Gregory</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:29089518</idno><idno type="pmid">29089518</idno><idno type="doi">10.1038/s41467-017-01344-3</idno><idno type="pmc">PMC5663706</idno><idno type="wicri:Area/Main/Corpus">000692</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000692</idno><idno type="wicri:Area/Main/Curation">000692</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000692</idno><idno type="wicri:Area/Main/Exploration">000692</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.</title><author><name sortKey="Wlodek, Aleksandra" sort="Wlodek, Aleksandra" uniqKey="Wlodek A" first="Aleksandra" last="Wlodek">Aleksandra Wlodek</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Kendrew, Steve G" sort="Kendrew, Steve G" uniqKey="Kendrew S" first="Steve G" last="Kendrew">Steve G. Kendrew</name><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Engineered Biodesign Limited, Cambridge, CB22 3GN, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Engineered Biodesign Limited, Cambridge, CB22 3GN</wicri:regionArea><wicri:noRegion>CB22 3GN</wicri:noRegion></affiliation></author><author><name sortKey="Coates, Nigel J" sort="Coates, Nigel J" uniqKey="Coates N" first="Nigel J" last="Coates">Nigel J. Coates</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Hold, Adam" sort="Hold, Adam" uniqKey="Hold A" first="Adam" last="Hold">Adam Hold</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Pogwizd, Joanna" sort="Pogwizd, Joanna" uniqKey="Pogwizd J" first="Joanna" last="Pogwizd">Joanna Pogwizd</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Rudder, Steven" sort="Rudder, Steven" uniqKey="Rudder S" first="Steven" last="Rudder">Steven Rudder</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Sheehan, Lesley S" sort="Sheehan, Lesley S" uniqKey="Sheehan L" first="Lesley S" last="Sheehan">Lesley S. Sheehan</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Higginbotham, Sarah J" sort="Higginbotham, Sarah J" uniqKey="Higginbotham S" first="Sarah J" last="Higginbotham">Sarah J. Higginbotham</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Stanley Smith, Anna E" sort="Stanley Smith, Anna E" uniqKey="Stanley Smith A" first="Anna E" last="Stanley-Smith">Anna E. Stanley-Smith</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Warneck, Tony" sort="Warneck, Tony" uniqKey="Warneck T" first="Tony" last="Warneck">Tony Warneck</name><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Nur E Alam, Mohammad" sort="Nur E Alam, Mohammad" uniqKey="Nur E Alam M" first="Mohammad" last="Nur-E-Alam">Mohammad Nur-E-Alam</name><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 12372, Saudi Arabia.</nlm:affiliation><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea>Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 12372</wicri:regionArea><wicri:noRegion>12372</wicri:noRegion></affiliation></author><author><name sortKey="Radzom, Markus" sort="Radzom, Markus" uniqKey="Radzom M" first="Markus" last="Radzom">Markus Radzom</name><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>BASF SE, Speyerer Str. 2, Limburgerhof, 67117, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>BASF SE, Speyerer Str. 2, Limburgerhof, 67117</wicri:regionArea><wicri:noRegion>67117</wicri:noRegion><wicri:noRegion>67117</wicri:noRegion><wicri:noRegion>67117</wicri:noRegion></affiliation></author><author><name sortKey="Martin, Christine J" sort="Martin, Christine J" uniqKey="Martin C" first="Christine J" last="Martin">Christine J. Martin</name><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Overvoorde, Lois" sort="Overvoorde, Lois" uniqKey="Overvoorde L" first="Lois" last="Overvoorde">Lois Overvoorde</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Samborskyy, Markiyan" sort="Samborskyy, Markiyan" uniqKey="Samborskyy M" first="Markiyan" last="Samborskyy">Markiyan Samborskyy</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Alt, Silke" sort="Alt, Silke" uniqKey="Alt S" first="Silke" last="Alt">Silke Alt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH</wicri:regionArea><wicri:noRegion>NR4 7UH</wicri:noRegion></affiliation></author><author><name sortKey="Heine, Daniel" sort="Heine, Daniel" uniqKey="Heine D" first="Daniel" last="Heine">Daniel Heine</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH</wicri:regionArea><wicri:noRegion>NR4 7UH</wicri:noRegion></affiliation></author><author><name sortKey="Carter, Guy T" sort="Carter, Guy T" uniqKey="Carter G" first="Guy T" last="Carter">Guy T. Carter</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Graziani, Edmund I" sort="Graziani, Edmund I" uniqKey="Graziani E" first="Edmund I" last="Graziani">Edmund I. Graziani</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Medicine Discovery Network-Synthetic Biology, Pfizer Worldwide R&D, 445 Eastern Point Rd., Groton, CT, 06340, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Medicine Discovery Network-Synthetic Biology, Pfizer Worldwide R&D, 445 Eastern Point Rd., Groton, CT, 06340</wicri:regionArea><wicri:noRegion>06340</wicri:noRegion></affiliation></author><author><name sortKey="Koehn, Frank E" sort="Koehn, Frank E" uniqKey="Koehn F" first="Frank E" last="Koehn">Frank E. Koehn</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Mcdonald, Leonard" sort="Mcdonald, Leonard" uniqKey="Mcdonald L" first="Leonard" last="Mcdonald">Leonard Mcdonald</name><affiliation wicri:level="1"><nlm:affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965</wicri:regionArea><wicri:noRegion>10965</wicri:noRegion></affiliation></author><author><name sortKey="Alanine, Alexander" sort="Alanine, Alexander" uniqKey="Alanine A" first="Alexander" last="Alanine">Alexander Alanine</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Rodriguez Sarmiento, Rosa Maria" sort="Rodriguez Sarmiento, Rosa Maria" uniqKey="Rodriguez Sarmiento R" first="Rosa María" last="Rodríguez Sarmiento">Rosa María Rodríguez Sarmiento</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Chao, Suzan Keen" sort="Chao, Suzan Keen" uniqKey="Chao S" first="Suzan Keen" last="Chao">Suzan Keen Chao</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Ratni, Hasane" sort="Ratni, Hasane" uniqKey="Ratni H" first="Hasane" last="Ratni">Hasane Ratni</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Steward, Lucinda" sort="Steward, Lucinda" uniqKey="Steward L" first="Lucinda" last="Steward">Lucinda Steward</name><affiliation wicri:level="1"><nlm:affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070</wicri:regionArea><wicri:noRegion>CH-4070</wicri:noRegion></affiliation></author><author><name sortKey="Norville, Isobel H" sort="Norville, Isobel H" uniqKey="Norville I" first="Isobel H" last="Norville">Isobel H. Norville</name><affiliation wicri:level="1"><nlm:affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Defence Science and Technology Laboratory, Porton Down, PO17 6AD</wicri:regionArea><wicri:noRegion>PO17 6AD</wicri:noRegion></affiliation></author><author><name sortKey="Sarkar Tyson, Mitali" sort="Sarkar Tyson, Mitali" uniqKey="Sarkar Tyson M" first="Mitali" last="Sarkar-Tyson">Mitali Sarkar-Tyson</name><affiliation wicri:level="1"><nlm:affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Defence Science and Technology Laboratory, Porton Down, PO17 6AD</wicri:regionArea><wicri:noRegion>PO17 6AD</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Monash Avenue, Nedlands, WA, 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Monash Avenue, Nedlands, WA, 6009</wicri:regionArea><wicri:noRegion>6009</wicri:noRegion></affiliation></author><author><name sortKey="Moss, Steven J" sort="Moss, Steven J" uniqKey="Moss S" first="Steven J" last="Moss">Steven J. Moss</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author><author><name sortKey="Leadlay, Peter F" sort="Leadlay, Peter F" uniqKey="Leadlay P" first="Peter F" last="Leadlay">Peter F. Leadlay</name><affiliation wicri:level="4"><nlm:affiliation>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wilkinson, Barrie" sort="Wilkinson, Barrie" uniqKey="Wilkinson B" first="Barrie" last="Wilkinson">Barrie Wilkinson</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK. barrie.wilkinson@jic.ac.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH</wicri:regionArea><wicri:noRegion>NR4 7UH</wicri:noRegion></affiliation></author><author><name sortKey="Gregory, Matthew A" sort="Gregory, Matthew A" uniqKey="Gregory M" first="Matthew A" last="Gregory">Matthew A. Gregory</name><affiliation wicri:level="1"><nlm:affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL</wicri:regionArea><wicri:noRegion>CB10 1XL</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nature communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Bioengineering (MeSH)</term><term>Biosynthetic Pathways (genetics)</term><term>Evolution, Molecular (MeSH)</term><term>Genetic Variation (MeSH)</term><term>Multigene Family (MeSH)</term><term>Polyketide Synthases (genetics)</term><term>Sirolimus (chemistry)</term><term>Sirolimus (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Bioingénierie (MeSH)</term><term>Famille multigénique (MeSH)</term><term>Polyketide synthases (génétique)</term><term>Sirolimus (composition chimique)</term><term>Sirolimus (métabolisme)</term><term>Variation génétique (MeSH)</term><term>Voies de biosynthèse (génétique)</term><term>Évolution moléculaire (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Sirolimus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Polyketide Synthases</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Biosynthetic Pathways</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Polyketide synthases</term><term>Voies de biosynthèse</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Sirolimus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Bioengineering</term><term>Evolution, Molecular</term><term>Genetic Variation</term><term>Multigene Family</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Bioingénierie</term><term>Famille multigénique</term><term>Variation génétique</term><term>Évolution moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29089518</PMID><DateCompleted><Year>2018</Year><Month>08</Month><Day>27</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2041-1723</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>1</Issue><PubDate><Year>2017</Year><Month>10</Month><Day>31</Day></PubDate></JournalIssue><Title>Nature communications</Title><ISOAbbreviation>Nat Commun</ISOAbbreviation></Journal><ArticleTitle>Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.</ArticleTitle><Pagination><MedlinePgn>1206</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/s41467-017-01344-3</ELocationID><Abstract><AbstractText>Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wlodek</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-5485-9978</Identifier><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kendrew</LastName><ForeName>Steve G</ForeName><Initials>SG</Initials><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Engineered Biodesign Limited, Cambridge, CB22 3GN, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coates</LastName><ForeName>Nigel J</ForeName><Initials>NJ</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hold</LastName><ForeName>Adam</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pogwizd</LastName><ForeName>Joanna</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rudder</LastName><ForeName>Steven</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sheehan</LastName><ForeName>Lesley S</ForeName><Initials>LS</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Higginbotham</LastName><ForeName>Sarah J</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stanley-Smith</LastName><ForeName>Anna E</ForeName><Initials>AE</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Warneck</LastName><ForeName>Tony</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nur-E-Alam</LastName><ForeName>Mohammad</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 12372, Saudi Arabia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radzom</LastName><ForeName>Markus</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>BASF SE, Speyerer Str. 2, Limburgerhof, 67117, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Christine J</ForeName><Initials>CJ</Initials><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Overvoorde</LastName><ForeName>Lois</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Samborskyy</LastName><ForeName>Markiyan</ForeName><Initials>M</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-6946-0385</Identifier><AffiliationInfo><Affiliation>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alt</LastName><ForeName>Silke</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Heine</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Carter</LastName><ForeName>Guy T</ForeName><Initials>GT</Initials><AffiliationInfo><Affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Graziani</LastName><ForeName>Edmund I</ForeName><Initials>EI</Initials><AffiliationInfo><Affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Medicine Discovery Network-Synthetic Biology, Pfizer Worldwide R&D, 445 Eastern Point Rd., Groton, CT, 06340, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Koehn</LastName><ForeName>Frank E</ForeName><Initials>FE</Initials><AffiliationInfo><Affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McDonald</LastName><ForeName>Leonard</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Chemical and Screening Sciences, Wyeth Pharmaceuticals, 401 North Middletown Road, Pearl River, NY, 10965, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alanine</LastName><ForeName>Alexander</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rodríguez Sarmiento</LastName><ForeName>Rosa María</ForeName><Initials>RM</Initials><AffiliationInfo><Affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chao</LastName><ForeName>Suzan Keen</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ratni</LastName><ForeName>Hasane</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steward</LastName><ForeName>Lucinda</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Roche Innovation Center Basel, Pharmaceutical Research and Early Development (PRED), Basel, CH-4070, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Norville</LastName><ForeName>Isobel H</ForeName><Initials>IH</Initials><AffiliationInfo><Affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sarkar-Tyson</LastName><ForeName>Mitali</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Defence Science and Technology Laboratory, Porton Down, PO17 6AD, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Monash Avenue, Nedlands, WA, 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Moss</LastName><ForeName>Steven J</ForeName><Initials>SJ</Initials><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leadlay</LastName><ForeName>Peter F</ForeName><Initials>PF</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wilkinson</LastName><ForeName>Barrie</ForeName><Initials>B</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-7646-7174</Identifier><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. barrie.wilkinson@jic.ac.uk.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK. barrie.wilkinson@jic.ac.uk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gregory</LastName><ForeName>Matthew A</ForeName><Initials>MA</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-4890-8977</Identifier><AffiliationInfo><Affiliation>Isomerase Therapeutics Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biotica Technology Ltd., Chesterford Research Park, Cambridge, CB10 1XL, UK. matt.gregory@isomerase.co.uk.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>BB/N023498/1</GrantID><Agency>Biotechnology and Biological Sciences Research Council</Agency><Country>United Kingdom</Country></Grant><Grant><GrantID>BB/M012158/1</GrantID><Agency>Biotechnology and Biological Sciences Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2017</Year><Month>10</Month><Day>31</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nat Commun</MedlineTA><NlmUniqueID>101528555</NlmUniqueID><ISSNLinking>2041-1723</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>79956-01-7</RegistryNumber><NameOfSubstance UI="D048630">Polyketide Synthases</NameOfSubstance></Chemical><Chemical><RegistryNumber>W36ZG6FT64</RegistryNumber><NameOfSubstance UI="D020123">Sirolimus</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D057005" MajorTopicYN="N">Bioengineering</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053898" MajorTopicYN="N">Biosynthetic Pathways</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019143" MajorTopicYN="Y">Evolution, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014644" MajorTopicYN="Y">Genetic Variation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005810" MajorTopicYN="Y">Multigene Family</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D048630" MajorTopicYN="N">Polyketide Synthases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020123" MajorTopicYN="N">Sirolimus</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2017</Year><Month>08</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2017</Year><Month>09</Month><Day>08</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2017</Year><Month>11</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2017</Year><Month>11</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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IdType="pubmed">24837284</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li><li>Arabie saoudite</li><li>Australie</li><li>Royaume-Uni</li><li>Suisse</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li></region><settlement><li>Cambridge</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Wlodek, Aleksandra" sort="Wlodek, Aleksandra" uniqKey="Wlodek A" first="Aleksandra" last="Wlodek">Aleksandra Wlodek</name></noRegion><name sortKey="Alt, Silke" sort="Alt, Silke" uniqKey="Alt S" first="Silke" last="Alt">Silke Alt</name><name sortKey="Coates, Nigel J" sort="Coates, Nigel J" uniqKey="Coates N" first="Nigel J" last="Coates">Nigel J. Coates</name><name sortKey="Coates, Nigel J" sort="Coates, Nigel J" uniqKey="Coates N" first="Nigel J" last="Coates">Nigel J. Coates</name><name sortKey="Gregory, Matthew A" sort="Gregory, Matthew A" uniqKey="Gregory M" first="Matthew A" last="Gregory">Matthew A. Gregory</name><name sortKey="Gregory, Matthew A" sort="Gregory, Matthew A" uniqKey="Gregory M" first="Matthew A" last="Gregory">Matthew A. Gregory</name><name sortKey="Heine, Daniel" sort="Heine, Daniel" uniqKey="Heine D" first="Daniel" last="Heine">Daniel Heine</name><name sortKey="Higginbotham, Sarah J" sort="Higginbotham, Sarah J" uniqKey="Higginbotham S" first="Sarah J" last="Higginbotham">Sarah J. Higginbotham</name><name sortKey="Hold, Adam" sort="Hold, Adam" uniqKey="Hold A" first="Adam" last="Hold">Adam Hold</name><name sortKey="Kendrew, Steve G" sort="Kendrew, Steve G" uniqKey="Kendrew S" first="Steve G" last="Kendrew">Steve G. Kendrew</name><name sortKey="Kendrew, Steve G" sort="Kendrew, Steve G" uniqKey="Kendrew S" first="Steve G" last="Kendrew">Steve G. Kendrew</name><name sortKey="Leadlay, Peter F" sort="Leadlay, Peter F" uniqKey="Leadlay P" first="Peter F" last="Leadlay">Peter F. Leadlay</name><name sortKey="Martin, Christine J" sort="Martin, Christine J" uniqKey="Martin C" first="Christine J" last="Martin">Christine J. Martin</name><name sortKey="Moss, Steven J" sort="Moss, Steven J" uniqKey="Moss S" first="Steven J" last="Moss">Steven J. Moss</name><name sortKey="Moss, Steven J" sort="Moss, Steven J" uniqKey="Moss S" first="Steven J" last="Moss">Steven J. Moss</name><name sortKey="Norville, Isobel H" sort="Norville, Isobel H" uniqKey="Norville I" first="Isobel H" last="Norville">Isobel H. Norville</name><name sortKey="Nur E Alam, Mohammad" sort="Nur E Alam, Mohammad" uniqKey="Nur E Alam M" first="Mohammad" last="Nur-E-Alam">Mohammad Nur-E-Alam</name><name sortKey="Overvoorde, Lois" sort="Overvoorde, Lois" uniqKey="Overvoorde L" first="Lois" last="Overvoorde">Lois Overvoorde</name><name sortKey="Pogwizd, Joanna" sort="Pogwizd, Joanna" uniqKey="Pogwizd J" first="Joanna" last="Pogwizd">Joanna Pogwizd</name><name sortKey="Radzom, Markus" sort="Radzom, Markus" uniqKey="Radzom M" first="Markus" last="Radzom">Markus Radzom</name><name sortKey="Rudder, Steven" sort="Rudder, Steven" uniqKey="Rudder S" first="Steven" last="Rudder">Steven Rudder</name><name sortKey="Samborskyy, Markiyan" sort="Samborskyy, Markiyan" uniqKey="Samborskyy M" first="Markiyan" last="Samborskyy">Markiyan Samborskyy</name><name sortKey="Sarkar Tyson, Mitali" sort="Sarkar Tyson, Mitali" uniqKey="Sarkar Tyson M" first="Mitali" last="Sarkar-Tyson">Mitali Sarkar-Tyson</name><name sortKey="Sheehan, Lesley S" sort="Sheehan, Lesley S" uniqKey="Sheehan L" first="Lesley S" last="Sheehan">Lesley S. Sheehan</name><name sortKey="Sheehan, Lesley S" sort="Sheehan, Lesley S" uniqKey="Sheehan L" first="Lesley S" last="Sheehan">Lesley S. Sheehan</name><name sortKey="Stanley Smith, Anna E" sort="Stanley Smith, Anna E" uniqKey="Stanley Smith A" first="Anna E" last="Stanley-Smith">Anna E. Stanley-Smith</name><name sortKey="Stanley Smith, Anna E" sort="Stanley Smith, Anna E" uniqKey="Stanley Smith A" first="Anna E" last="Stanley-Smith">Anna E. Stanley-Smith</name><name sortKey="Warneck, Tony" sort="Warneck, Tony" uniqKey="Warneck T" first="Tony" last="Warneck">Tony Warneck</name><name sortKey="Wilkinson, Barrie" sort="Wilkinson, Barrie" uniqKey="Wilkinson B" first="Barrie" last="Wilkinson">Barrie Wilkinson</name><name sortKey="Wilkinson, Barrie" sort="Wilkinson, Barrie" uniqKey="Wilkinson B" first="Barrie" last="Wilkinson">Barrie Wilkinson</name><name sortKey="Wilkinson, Barrie" sort="Wilkinson, Barrie" uniqKey="Wilkinson B" first="Barrie" last="Wilkinson">Barrie Wilkinson</name></country><country name="Arabie saoudite"><noRegion><name sortKey="Nur E Alam, Mohammad" sort="Nur E Alam, Mohammad" uniqKey="Nur E Alam M" first="Mohammad" last="Nur-E-Alam">Mohammad Nur-E-Alam</name></noRegion></country><country name="Allemagne"><noRegion><name sortKey="Radzom, Markus" sort="Radzom, Markus" uniqKey="Radzom M" first="Markus" last="Radzom">Markus Radzom</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Carter, Guy T" sort="Carter, Guy T" uniqKey="Carter G" first="Guy T" last="Carter">Guy T. Carter</name></noRegion><name sortKey="Graziani, Edmund I" sort="Graziani, Edmund I" uniqKey="Graziani E" first="Edmund I" last="Graziani">Edmund I. Graziani</name><name sortKey="Graziani, Edmund I" sort="Graziani, Edmund I" uniqKey="Graziani E" first="Edmund I" last="Graziani">Edmund I. Graziani</name><name sortKey="Koehn, Frank E" sort="Koehn, Frank E" uniqKey="Koehn F" first="Frank E" last="Koehn">Frank E. Koehn</name><name sortKey="Mcdonald, Leonard" sort="Mcdonald, Leonard" uniqKey="Mcdonald L" first="Leonard" last="Mcdonald">Leonard Mcdonald</name></country><country name="Suisse"><noRegion><name sortKey="Alanine, Alexander" sort="Alanine, Alexander" uniqKey="Alanine A" first="Alexander" last="Alanine">Alexander Alanine</name></noRegion><name sortKey="Chao, Suzan Keen" sort="Chao, Suzan Keen" uniqKey="Chao S" first="Suzan Keen" last="Chao">Suzan Keen Chao</name><name sortKey="Ratni, Hasane" sort="Ratni, Hasane" uniqKey="Ratni H" first="Hasane" last="Ratni">Hasane Ratni</name><name sortKey="Rodriguez Sarmiento, Rosa Maria" sort="Rodriguez Sarmiento, Rosa Maria" uniqKey="Rodriguez Sarmiento R" first="Rosa María" last="Rodríguez Sarmiento">Rosa María Rodríguez Sarmiento</name><name sortKey="Steward, Lucinda" sort="Steward, Lucinda" uniqKey="Steward L" first="Lucinda" last="Steward">Lucinda Steward</name></country><country name="Australie"><noRegion><name sortKey="Sarkar Tyson, Mitali" sort="Sarkar Tyson, Mitali" uniqKey="Sarkar Tyson M" first="Mitali" last="Sarkar-Tyson">Mitali Sarkar-Tyson</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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