Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement

Nature. 2013 Nov 28;503(7477):552-556. doi: 10.1038/nature12643. Epub 2013 Oct 27.

Abstract

Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(β-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.

Publication types

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

MeSH terms

  • Anti-Bacterial Agents / biosynthesis
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Biocatalysis
  • Bridged-Ring Compounds / metabolism
  • Crystallography, X-Ray
  • Cyclization
  • Flavins / metabolism*
  • Flavoproteins / chemistry
  • Flavoproteins / metabolism*
  • Isotope Labeling
  • Mixed Function Oxygenases / chemistry
  • Mixed Function Oxygenases / metabolism*
  • Models, Chemical
  • Models, Molecular
  • Oxidation-Reduction
  • Polyketides / metabolism
  • Protein Conformation
  • Streptomyces / enzymology*
  • Streptomyces / metabolism
  • Substrate Specificity

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Bridged-Ring Compounds
  • Flavins
  • Flavoproteins
  • Polyketides
  • enterocin
  • Mixed Function Oxygenases

Associated data

  • PDB/3W8W
  • PDB/3W8X
  • PDB/3W8Z