De Novo Design and Implementation of a Tandem Acyl Carrier Protein Domain in a Type i Modular Polyketide Synthase

Zilong Wang, Saket R. Bagde, Gerardo Zavala, Tsutomu Matsui, Xi Chen, Chu Young Kim

Research output: Contribution to journalArticlepeer-review

Abstract

During polyketide and fatty acid biosynthesis, the growing acyl chain is attached to the acyl carrier protein via a thioester linkage. The acyl carrier protein interacts with other enzymes that perform chain elongation and chain modification on the bound acyl chain. Most type I polyketide synthases and fatty acid synthases contain only one acyl carrier protein. However, polyunsaturated fatty acid synthases from deep-sea bacteria contain anywhere from two to nine acyl carrier proteins. Recent studies have shown that this tandem acyl carrier protein feature is responsible for the unusually high fatty acid production rate of deep-sea bacteria. To investigate if a similar strategy can be used to increase the production rate of type I polyketide synthases, a 3×ACP domain was rationally designed and genetically installed in module 6 of 6-deoxyerythronolide B synthase, which is a prototypical type I modular polyketide synthase that naturally harbors just one acyl carrier protein. This modification resulted in an ∼2.5-fold increase in the total amount of polyketide produced in vitro, demonstrating that installing a tandem acyl carrier domain in a type I polyketide synthase is an effective strategy for enhancing the rate of polyketide natural product biosynthesis.

Original languageEnglish (US)
Pages (from-to)3072-3077
Number of pages6
JournalACS chemical biology
Volume13
Issue number11
DOIs
StatePublished - Nov 16 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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