Substrate-Assisted Catalysis in Polyketide Reduction Proceeds via a Phenolate Intermediate

Cell Chem Biol. 2016 Sep 22;23(9):1091-1097. doi: 10.1016/j.chembiol.2016.07.018. Epub 2016 Sep 8.


SimC7 is a polyketide ketoreductase involved in biosynthesis of the angucyclinone moiety of the gyrase inhibitor simocyclinone D8 (SD8). SimC7, which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily, catalyzes reduction of the C-7 carbonyl of the angucyclinone, and the resulting hydroxyl is essential for antibiotic activity. SimC7 shares little sequence similarity with characterized ketoreductases, suggesting it might have a distinct mechanism. To investigate this possibility, we determined the structures of SimC7 alone, with NADP(+), and with NADP(+) and the substrate 7-oxo-SD8. These structures show that SimC7 is distinct from previously characterized polyketide ketoreductases, lacking the conserved catalytic triad, including the active-site tyrosine that acts as central acid-base catalyst in canonical SDR proteins. Taken together with functional analyses of active-site mutants, our data suggest that SimC7 catalyzes a substrate-assisted, two-step reaction for reduction of the C-7 carbonyl group involving intramolecular transfer of a substrate-derived proton to generate a phenolate intermediate.

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / chemistry
  • Alcohol Oxidoreductases / metabolism*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Biocatalysis*
  • Coumarins / pharmacology
  • Glycosides / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Phenols / chemistry
  • Phenols / metabolism*
  • Point Mutation
  • Polyketides / chemistry
  • Polyketides / metabolism*
  • Substrate Specificity


  • Bacterial Proteins
  • Coumarins
  • Glycosides
  • Phenols
  • Polyketides
  • simocyclinone D8
  • Alcohol Oxidoreductases
  • polyketide synthase ketoreductase