Cobalt-sulfur coordination chemistry drives B₁₂ loading onto methionine synthase

Authors

Romila Mascarenhas, University of Michigan, Ann Arbor
Arkajit Guha, University of Michigan, Ann Arbor
Zhu Li, University of Michigan, Ann Arbor
Markus Ruetz, University of Michigan, Ann Arbor
Sojin An, University of Michigan, Ann Arbor
Javier Seravalli, University of Nebraska-Lincoln
Ruma Banerjee, University of Michigan, Ann Arbor

Document Type

Article

Date of this Version

7-26-2023

Citation

Published (2023) Journal of the American Chemical Society, . DOI: 10.1021/jacs.3c07941

Comments

Used by permission.

Abstract

Cobalt-sulfur (Co-S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in Nature. Cobalamin (or vitamin B12) is an essential cobalt-containing organometallic cofactor in mammals, and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co-S coordination, for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the -axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.