Radical S-Adenosyl-l-methionine Tryptophan Lyase (NosL): How the Protein Controls the Carboxyl Radical •CO 2- Migration

J Am Chem Soc. 2018 Dec 5;140(48):16661-16668. doi: 10.1021/jacs.8b09142. Epub 2018 Nov 16.

Abstract

The radical S-adenosyl-l-methionine tryptophan lyase uses radical-based chemistry to convert l-tryptophan into 3-methyl-2-indolic acid, a fragment in the biosynthesis of the thiopeptide antibiotic nosiheptide. This complex reaction involves several successive steps corresponding to (i) the activation by a specific hydrogen-atom abstraction, (ii) an unprecedented •CO2- radical migration, (iii) a cyanide fragment release, and (iv) the termination of the radical-based reaction. In vitro study of this reaction is made more difficult because the enzyme produces a significant amount of a shunt product instead of the natural product. Here, using a combination of X-ray crystallography, electron paramagnetic resonance spectroscopy, and quantum and hybrid quantum mechanical/molecular mechanical calculations, we have deciphered the fine mechanism of the key •CO2- radical migration, highlighting how the preorganized active site of the protein tightly controls this reaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Carbon-Carbon Lyases / chemistry
  • Carbon-Carbon Lyases / metabolism*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Decarboxylation
  • Electron Spin Resonance Spectroscopy
  • Free Radicals / chemistry
  • Models, Molecular
  • Protein Binding
  • Quantum Theory
  • Streptomyces / enzymology
  • Tryptophan / chemistry
  • Tryptophan / metabolism*

Substances

  • Bacterial Proteins
  • Free Radicals
  • Tryptophan
  • Carbon-Carbon Lyases
  • S-adenosyl-L-methionine tryptophan lyase, Streptomyces actuosus