Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Abstract

Cobalt−sulfur (Co−S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in nature. Cobalamin (or vitamin B 12 ) 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 β-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.

Electrocatalytic Reduction of Disulfide Bonds in Antibodies

“…31,32 To further elucidate the mechanism for electrocatalytic disulfide reduction, we focused on VB 12 since several potential catalytic intermediates have been reported. 33,34 We observed that the reaction between the electrochemically generated reduced Co(I) species and excess 1 yields the previously characterized Co(III)-cysteine adduct by UV-Vis spectroscopy (Figure 2B). 35 Based on the established VB 12 reactivity, [36][37][38] the Co(I) most likely reacts via nucleophilic attack on the disulfide, pushing the two electrons of the disulfide bond to the leaving thiolate.…”