Insight into the mechanism of biological methanol activation based on the 
crystal structure of the methanol-cobalamin methyltransferase complex

Hagemeier, Christoph H.; Krüer, Markus; Thauer, Rudolf; Warkentin, Eberhard; Ermler, Ulrich

doi:10.1073/pnas.0603650103

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Insight into the mechanism of biological methanol activation based on the crystal structure of the methanol-cobalamin methyltransferase complex

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Warkentin, Eberhard
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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

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Citation

Hagemeier, C. H., Krüer, M., Thauer, R., Warkentin, E., & Ermler, U. (2006). Insight into the mechanism of biological methanol activation based on the crystal structure of the methanol-cobalamin methyltransferase complex. Proceedings of the National Academy of Sciences of the United States of America, 103(50), 18917-18922. doi:10.1073/pnas.0603650103.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-D8FD-9

Abstract

Some methanogenic and acetogenic microorganisms have the catalytic capability to cleave heterolytically the CO^--O bond of methanol. To obtain insight into the elusive enzymatic mechanism of this challenging chemical reaction we have investigated the methanol-activating MtaBC complex from Methanosarcina barkericomposed of the zinc-containing MtaB and the 5-hydroxybenzimi-dazolylcobamide-carrying MtaC subunits. Here we report the 2.5-Åcrystal structure of this complex organized as a (MtaBC)₂ heterotetramer. MtaB folds as a TIM barrel and contains a novel zinc-binding motif. Zinc(II) lies at the bottom of a funnel formed at the C-terminal β-barrel end and ligates to two cysteinyl sulfurs (Cys-220and Cys-269) and one carboxylate oxygen (Glu-164). MtaC is structurally related to the cobalamin-binding domain of methio-nine synthase. Its corrinoid cofactor at the top of the Rossmann domain reaches deeply into the funnel of MtaB, defining a regionbetween zinc(II) and the corrinoid cobalt that must be the binding site for methanol. The active site geometry supports a S_N2 reaction mechanism, in which the CO^--O bond in methanol is activated by the strong electrophile zinc(II) and cleaved because of an attack of the supernucleophile cob(I)amide. The environment of zinc(II) is characterized by an acidic cluster that increases the charge density onthe zinc(II), polarizes methanol, and disfavors deprotonation of the methanol hydroxyl group. Implications of the MtaBC structure for the second step of the reaction, in which the methyl group is transferred to coenzyme M, are discussed.