Crystallographic snapshots of a B12-dependent radical SAM methyltransferase

Cameron D. Fyfe, Noelia Bernardo-García, Laura Fradale, Stéphane Grimaldi, Alain Guillot, Clémence Brewee, Leonard M. G. Chavas, Pierre Legrand, Alhosna Benjdia () and Olivier Berteau ()
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Cameron D. Fyfe: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Noelia Bernardo-García: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Laura Fradale: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Stéphane Grimaldi: Aix Marseille Univ, CNRS, BIP UMR7281
Alain Guillot: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Clémence Brewee: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Leonard M. G. Chavas: Synchrotron SOLEIL, HelioBio group, L’Orme des Merisiers
Pierre Legrand: Synchrotron SOLEIL, HelioBio group, L’Orme des Merisiers
Alhosna Benjdia: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio
Olivier Berteau: Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, ChemSyBio

Nature, 2022, vol. 602, issue 7896, 336-342

Abstract: Abstract By catalysing the microbial formation of methane, methyl-coenzyme M reductase has a central role in the global levels of this greenhouse gas1,2. The activity of methyl-coenzyme M reductase is profoundly affected by several unique post-translational modifications3–6, such as a unique C-methylation reaction catalysed by methanogenesis marker protein 10 (Mmp10), a radical S-adenosyl-l-methionine (SAM) enzyme7,8. Here we report the spectroscopic investigation and atomic resolution structure of Mmp10 from Methanosarcina acetivorans, a unique B12 (cobalamin)-dependent radical SAM enzyme9. 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 B12-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 B12-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.

Date: 2022
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DOI: 10.1038/s41586-021-04355-9

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