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

Fujishiro, Takashi; Bai , Liping; Xu , Tao; Xie , Xiulan; Schick, Michael; Kahnt, Jörg; Rother, Michael; Hu , Xile; Ermler, Ulrich; Shima, Seigo

doi:DOI: 10.1002/anie.201604352

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

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Ermler, Ulrich
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Fujishiro, T., Bai, L., Xu, T., Xie, X., Schick, M., Kahnt, J., et al. (2016). Identification of HcgC as a SAM-Dependent Pyridinol Methyltransferase in [Fe]-Hydrogenase Cofactor Biosynthesis. Angewandte Chemie International Edition in English, 55(33), 9648-9651. doi:DOI: 10.1002/anie.201604352.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002D-1D06-E

Abstract

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