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.