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A Water‐Bridged H‐Bonding Network Contributes to the Catalysis of the SAM‐Dependent C‐Methyltransferase HcgC
Author(s) -
Bai Liping,
Wagner Tristan,
Xu Tao,
Hu Xile,
Ermler Ulrich,
Shima Seigo
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201705605
Subject(s) - methyltransferase , catalysis , chemistry , o methyltransferase , stereochemistry , biochemistry , methylation , dna
[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 Å 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.