Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products

Chembiochem. 2023 Nov 2;24(21):e202300386. doi: 10.1002/cbic.202300386. Epub 2023 Sep 15.

Abstract

Polyketide natural products have significant promise as pharmaceutical targets for human health and as molecular tools to probe disease and complex biological systems. While the biosynthetic logic of polyketide synthases (PKS) is well-understood, biosynthesis of designer polyketides remains challenging due to several bottlenecks, including substrate specificity constraints, disrupted protein-protein interactions, and protein solubility and folding issues. Focusing on substrate specificity, PKSs are typically interrogated using synthetic thioesters. PKS assembly lines and their products offer a wealth of information when studied in a chemoenzymatic fashion. This review provides an overview of the past two decades of polyketide chemoenzymatic synthesis and their contributions to the field of chemical biology. These synthetic strategies have successfully yielded natural product derivatives while providing critical insights into enzymatic promiscuity and mechanistic activity.

Keywords: bioorganic chemistry; biosynthesis; enzymes; polyketides; synthetic biology.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Products* / metabolism
  • Humans
  • Polyketide Synthases / metabolism
  • Polyketides* / chemistry
  • Secondary Metabolism
  • Substrate Specificity

Substances

  • Polyketides
  • Biological Products
  • Polyketide Synthases