Aminoperoxide adducts expand the catalytic repertoire of flavin monooxygenases

Nat Chem Biol. 2020 May;16(5):556-563. doi: 10.1038/s41589-020-0476-2. Epub 2020 Feb 17.

Abstract

One of the hallmark reactions catalyzed by flavin-dependent enzymes is the incorporation of an oxygen atom derived from dioxygen into organic substrates. For many decades, these flavin monooxygenases were assumed to use exclusively the flavin-C4a-(hydro)peroxide as their oxygen-transferring intermediate. We demonstrate that flavoenzymes may instead employ a flavin-N5-peroxide as a soft α-nucleophile for catalysis, which enables chemistry not accessible to canonical monooxygenases. This includes, for example, the redox-neutral cleavage of carbon-hetero bonds or the dehalogenation of inert environmental pollutants via atypical oxygenations. We furthermore identify a shared structural motif for dioxygen activation and N5-functionalization, suggesting a conserved pathway that may be operative in numerous characterized and uncharacterized flavoenzymes from diverse organisms. Our findings show that overlooked flavin-N5-oxygen adducts are more widespread and may facilitate versatile chemistry, thus upending the notion that flavin monooxygenases exclusively function as nature's equivalents to organic peroxides in synthetic chemistry.

Publication types

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

MeSH terms

  • Biocatalysis
  • Crystallography, X-Ray
  • Dinitrocresols / chemistry
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism
  • Nitrogen / chemistry
  • Oxygen / chemistry
  • Oxygenases / chemistry*
  • Oxygenases / metabolism
  • Peroxides / chemistry
  • Phylogeny

Substances

  • Dinitrocresols
  • Escherichia coli Proteins
  • Peroxides
  • 4,6-dinitro-o-cresol
  • Oxygenases
  • Ruta protein, E coli
  • dimethylaniline monooxygenase (N-oxide forming)
  • dibenzothiophene sulfone monooxygenase
  • Nitrogen
  • Oxygen