Stereoselective C-C Bond Formation Catalysed by Engineered Carboxymethylproline Synthases

Nat Chem. 2011 May;3(5):365-71. doi: 10.1038/nchem.1011. Epub 2011 Apr 3.

Abstract

The reaction of enol(ate)s with electrophiles is used extensively in organic synthesis for stereoselective C-C bond formation. Protein-based catalysts have had comparatively limited application for the stereoselective formation of C-C bonds of choice via enolate chemistry. We describe protein engineering studies on 5-carboxymethylproline synthases, members of the crotonase superfamily, aimed at enabling stereoselective C-C bond formation leading to N-heterocycles via control of trisubstituted enolate intermediates. Active site substitutions, including at the oxyanion binding site, enable the production of substituted N-heterocycles in high diastereomeric excesses via stereocontrolled enolate formation and reaction. The results reveal the potential of the ubiquitous crotonase superfamily as adaptable catalysts for the control of enolate chemistry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carbon / metabolism*
  • Carbon-Carbon Lyases / chemistry
  • Carbon-Carbon Lyases / metabolism*
  • Catalysis
  • Catalytic Domain
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Engineering*
  • Sequence Homology, Amino Acid

Substances

  • Carbon
  • Carbon-Carbon Lyases
  • carboxymethylproline synthase

Associated data

  • PubChem-Substance/113585214
  • PubChem-Substance/113585215
  • PubChem-Substance/113585216
  • PubChem-Substance/113585217
  • PubChem-Substance/113585218
  • PubChem-Substance/113585219
  • PubChem-Substance/113585220
  • PubChem-Substance/113585221
  • PubChem-Substance/113585222
  • PubChem-Substance/113585223
  • PubChem-Substance/113585224
  • PubChem-Substance/113585225
  • PubChem-Substance/113585226
  • PubChem-Substance/113585227