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. KoehnLeonard 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, Matthew A. Gregory

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Article number1206
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

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