A Noble Metal Substitution Leads to B Cofactor Mimicry by a Rhodibalamin.

In mammals, cobalamin is an essential cofactor that is delivered by a multitude of chaperones in an elaborate trafficking pathway to two client enzymes, methionine synthase and methylmalonyl-CoA mutase (MMUT). Rhodibalamins, the rhodium analogs of cobalamins, have been described as antimetabolites due to their ability to inhibit bacterial growth. In this study, we have examined the reactivity of adenosylrhodibalamin (AdoRhbl) with two key human chaperones, MMACHC (also known as CblC) and adenosyltransferase (MMAB, also known as ATR), and with the human and MMUT.

Cobalt-Sulfur Coordination Chemistry Drives B Loading onto Methionine Synthase.

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

Cobalt-sulfur coordination chemistry drives B loading onto methionine synthase.

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

Coordination Chemistry Controls Coenzyme B Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase.

Cobalamin (or vitamin B)-dependent enzymes and trafficking chaperones exploit redox-linked coordination chemistry to control the cofactor reactivity during catalysis and translocation. As the cobalt oxidation state decreases from 3+ to 1+, the preferred cobalamin geometry changes from six- to four-coordinate (4-c). In this study, we reveal the sizable thermodynamic gain that accrues for human adenosine triphosphate (ATP):cob(I)alamin adenosyltransferase (or MMAB) by enforcing an unfavorable 4-c cob(II)alamin geometry.

Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B delivery and repair.

G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood.