Over 90% of Earth's methane is produced by the enzyme methyl-coenzyme M (methyl-SCoM) reductase (MCR) in methanogenic archaea. Using a nickel cofactor in the active site, MCR converts methyl-SCoM and coenzyme B (CoBSH) to methane and the mixed disulfide CoBS-SCoM. Two mechanisms have been proposed for this reaction, distinguished by their expected first intermediates: an organometallic methyl–Ni(III) complex or a methyl radical. To slow the reaction, enabling accumulation and observation of the intermediate, Wongnate et al. used a CoBSH analog with a shorter side chain. Through a combination of stopped-flow studies, rapid chemical and freeze quenching, and spectroscopy, the authors characterized this key intermediate and the kinetics of the reaction. These experiments, supported by quantum chemical calculations and molecular dynamics simulations, led them to propose a reaction mechanism wherein the first step consists of Ni(I) attack on methyl-SCoM to generate a methyl radical and a Ni(II)–thiolate complex. The methyl radical then abstracts a hydrogen atom from CoBSH, producing methane and the CoBS• radical, which combines with the Ni(II)-bound thiolate. The greater understanding of the enzyme mechanism afforded by this study should benefit the development of technologies to generate and activate methane, which is an energy source as well as a greenhouse gas.
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Deane, C. A radical approach. Nat Chem Biol 12, 467 (2016). https://doi.org/10.1038/nchembio.2122