Mapping the catalytic conformations of an assembly-line polyketide synthase module

Science. 2021 Nov 5;374(6568):729-734. doi: 10.1126/science.abi8358. Epub 2021 Nov 4.


Assembly-line polyketide synthases, such as the 6-deoxyerythronolide B synthase (DEBS), are large enzyme factories prized for their ability to produce specific and complex polyketide products. By channeling protein-tethered substrates across multiple active sites in a defined linear sequence, these enzymes facilitate programmed small-molecule syntheses that could theoretically be harnessed to access countless polyketide product structures. Using cryogenic electron microscopy to study DEBS module 1, we present a structural model describing this substrate-channeling phenomenon. Our 3.2- to 4.3-angstrom-resolution structures of the intact module reveal key domain-domain interfaces and highlight an unexpected module asymmetry. We also present the structure of a product-bound module that shines light on a recently described “turnstile” mechanism for transient gating of active sites along the assembly line.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biocatalysis
  • Catalytic Domain
  • Cryoelectron Microscopy
  • Models, Molecular
  • Polyketide Synthases / chemistry*
  • Polyketide Synthases / metabolism
  • Protein Conformation
  • Protein Domains
  • Saccharopolyspora / enzymology


  • Polyketide Synthases