Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 36, Pages 10806-10809Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201705605
Keywords
biosynthesis; enzyme mechanisms; methyltransferases; mutagenesis; protein structures
Categories
Funding
- Max Planck Society
- Deutsch Forschunggemeinschaft Priority Program Iron-Sulfur for Life [SH87/1-1]
- Swiss National Science Foundation [200020_152850/1, 200020_172486/1]
- China Scholarship Council (CSC)
- Swiss National Science Foundation (SNF) [200020_172486, 200020_152850] Funding Source: Swiss National Science Foundation (SNF)
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[Fe]-hydrogenase hosts an iron-guanylylpyridinol (FeGP) cofactor. The FeGP cofactor contains a pyridinol ring substituted with GMP, two methyl groups, and an acylmethyl group. HcgC, an enzyme involved in FeGP biosynthesis, catalyzes methyl transfer from S-adenosylmethionine (SAM) to C3 of 6-carboxymethyl-5-methyl-4-hydroxy-2-pyridinol (2). We report on the ternary structure of HcgC/S-adenosylhomocysteine (SAH, the demethylated product of SAM) and 2 at 1.7 angstrom resolution. The proximity of C3 of substrate 2 and the S atom of SAH indicates a catalytically productive geometry. The hydroxy and carboxy groups of substrate 2 are hydrogen-bonded with I115 and T179, as well as through a series of water molecules linked with polar and a few protonatable groups. These interactions stabilize the deprotonated state of the hydroxy groups and a keto form of substrate 2, through which the nucleophilicity of C3 is increased by resonance effects. Complemented by mutational analysis, a structure-based catalytic mechanism was proposed.
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