Crystallographic snapshots of a B12-dependent radical SAM methyltransferase

By catalysing the microbial formation of methane, methyl-coenzyme M reductase has a central role in the global levels of this greenhouse gas(1,2). The activity of methyl-coenzyme M reductase is profoundly affected by several unique post-translational modifications(3-6), such as a unique C-methylation reaction catalysed by methanogenesis marker protein 10 (Mmp10), a radical S-adenosyl-l-methionine (SAM) enzyme(7,8). Here we report the spectroscopic investigation and atomic resolution structure of Mmp10 from Methanosarcina acetivorans, a unique B-12 (cobalamin)-dependent radical SAM enzyme(9). The structure of Mmp10 reveals a unique enzyme architecture with four metallic centres and critical structural features involved in the control of catalysis. In addition, the structure of the enzyme-substrate complex offers a glimpse into a B-12-dependent radical SAM enzyme in a precatalytic state. By combining electron paramagnetic resonance spectroscopy, structural biology and biochemistry, our study illuminates the mechanism by which the emerging superfamily of B-12-dependent radical SAM enzymes catalyse chemically challenging alkylation reactions and identifies distinctive active site rearrangements to provide a structural rationale for the dual use of the SAM cofactor for radical and nucleophilic chemistry.

Automated summary

Methyl-coenzyme M reductase plays a central role in regulating global methane levels. The study of Methanosarcina acetivorans' Mmp10 provides insights into its unique enzyme structure and catalytic control mechanism, as well as the structural changes prior to catalysis. This research is important for understanding the catalytic mechanism of the emerging superfamily of B-12-dependent radical SAM enzymes.