Diversity oriented biosynthesis via accelerated evolution of modular gene clusters

Aleksandra Wlodek, Steve G. Kendrew, Nigel J. Coates, Adam Hold, Joanna Pogwizd, Steven Rudder, Lesley S. Sheehan, Sarah J. Higginbotham, Anna E. Stanley-Smith, Tony Warneck, Mohammad Nur-E-Alam, Markus Radzom, Christine J. Martin, Lois Overvoorde, Markiyan Samborskyy, Silke Alt, Daniel Heine, Guy T. Carter, Edmund I. Graziani, Frank E. Koehn, Leonard McDonald, Alexander Alanine, Rosa María Rodríguez Sarmiento, Suzan Keen Chao, Hasane Ratni, Lucinda Steward, Isobel H. Norville, Mitali Sarkar-Tyson, Steven J. Moss, Peter F. Leadlay, Barrie Wilkinson () and Matthew A. Gregory ()
Additional contact information
Aleksandra Wlodek: Isomerase Therapeutics Ltd., Chesterford Research Park
Steve G. Kendrew: Biotica Technology Ltd., Chesterford Research Park
Nigel J. Coates: Isomerase Therapeutics Ltd., Chesterford Research Park
Adam Hold: Isomerase Therapeutics Ltd., Chesterford Research Park
Joanna Pogwizd: Isomerase Therapeutics Ltd., Chesterford Research Park
Steven Rudder: Isomerase Therapeutics Ltd., Chesterford Research Park
Lesley S. Sheehan: Isomerase Therapeutics Ltd., Chesterford Research Park
Sarah J. Higginbotham: Isomerase Therapeutics Ltd., Chesterford Research Park
Anna E. Stanley-Smith: Isomerase Therapeutics Ltd., Chesterford Research Park
Tony Warneck: Biotica Technology Ltd., Chesterford Research Park
Mohammad Nur-E-Alam: Biotica Technology Ltd., Chesterford Research Park
Markus Radzom: Biotica Technology Ltd., Chesterford Research Park
Christine J. Martin: Biotica Technology Ltd., Chesterford Research Park
Lois Overvoorde: Isomerase Therapeutics Ltd., Chesterford Research Park
Markiyan Samborskyy: University of Cambridge
Silke Alt: John Innes Centre, Norwich Research Park
Daniel Heine: John Innes Centre, Norwich Research Park
Guy T. Carter: Wyeth Pharmaceuticals
Edmund I. Graziani: Wyeth Pharmaceuticals
Frank E. Koehn: Wyeth Pharmaceuticals
Leonard McDonald: Wyeth Pharmaceuticals
Alexander Alanine: Pharmaceutical Research and Early Development (PRED)
Rosa María Rodríguez Sarmiento: Pharmaceutical Research and Early Development (PRED)
Suzan Keen Chao: Pharmaceutical Research and Early Development (PRED)
Hasane Ratni: Pharmaceutical Research and Early Development (PRED)
Lucinda Steward: Pharmaceutical Research and Early Development (PRED)
Isobel H. Norville: Defence Science and Technology Laboratory
Mitali Sarkar-Tyson: Defence Science and Technology Laboratory
Steven J. Moss: Isomerase Therapeutics Ltd., Chesterford Research Park
Peter F. Leadlay: University of Cambridge
Barrie Wilkinson: Isomerase Therapeutics Ltd., Chesterford Research Park
Matthew A. Gregory: Isomerase Therapeutics Ltd., Chesterford Research Park

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01344-3

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DOI: 10.1038/s41467-017-01344-3

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