4.8 Article

Identification of HcgC as a SAM-Dependent Pyridinol Methyltransferase in [Fe]-Hydrogenase Cofactor Biosynthesis

Journal

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 33, Pages 9648-9651

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201604352

Keywords

cofactors; enzymes; hydrogenases; methyltransferases; protein structures

Funding

  1. Max Planck Society
  2. PRESTO program of the Japan Science and Technology Agency
  3. Swiss National Science Foundation [200020_152850/1]
  4. Swiss National Science Foundation (SNF) [200020_152850] Funding Source: Swiss National Science Foundation (SNF)

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Previous retrosynthetic and isotope-labeling studies have indicated that biosynthesis of the iron guanylylpyridinol (FeGP) cofactor of [Fe]-hydrogenase requires a methyltransferase. This hypothetical enzyme covalently attaches the methyl group at the 3-position of the pyridinol ring. We describe the identification of HcgC, a gene product of the hcgA-G cluster responsible for FeGP cofactor biosynthesis. It acts as an S-adenosylmethionine (SAM)-dependent methyltransferase, based on the crystal structures of HcgC and the HcgC/SAM and HcgC/S-adenosylhomocysteine (SAH) complexes. The pyridinol substrate, 6-carboxymethyl-5-methyl-4-hydroxy-2-pyridinol, was predicted based on properties of the conserved binding pocket and substrate docking simulations. For verification, the assumed substrate was synthesized and used in a kinetic assay. Mass spectrometry and NMR analysis revealed 6-carboxymethyl-3,5-dimethyl-4-hydroxy-2-pyridinol as the reaction product, which confirmed the function of HcgC.

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