Flavin-dependent halogenases catalyze enantioselective olefin halocyclization

Nat Commun. 2021 Jun 1;12(1):3268. doi: 10.1038/s41467-021-23503-3.

Abstract

Halocyclization of alkenes is a powerful bond-forming tool in synthetic organic chemistry and a key step in natural product biosynthesis, but catalyzing halocyclization with high enantioselectivity remains a challenging task. Identifying suitable enzymes that catalyze enantioselective halocyclization of simple olefins would therefore have significant synthetic value. Flavin-dependent halogenases (FDHs) catalyze halogenation of arene and enol(ate) substrates. Herein, we reveal that FDHs engineered to catalyze site-selective aromatic halogenation also catalyze non-native bromolactonization of olefins with high enantioselectivity and near-native catalytic proficiency. Highly selective halocyclization is achieved by characterizing and mitigating the release of HOBr from the FDH active site using a combination of reaction optimization and protein engineering. The structural origins of improvements imparted by mutations responsible for the emergence of halocyclase activity are discussed. This expansion of FDH catalytic activity presages the development of a wide range of biocatalytic halogenation reactions.

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

  • Alkenes / chemistry
  • Alkenes / metabolism*
  • Biocatalysis*
  • Catalytic Domain / genetics
  • Cyclization
  • Enzyme Assays
  • Flavins / chemistry
  • Flavins / metabolism*
  • Halogenation
  • Kinetics
  • Molecular Docking Simulation
  • Mutagenesis
  • Mutation
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Protein Engineering
  • Stereoisomerism

Substances

  • Alkenes
  • Flavins
  • Oxidoreductases
  • tryptophan halogenase