Cobalt Ins and Outs

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Science  18 Dec 2009:
Vol. 326, Issue 5960, pp. 1591
DOI: 10.1126/science.326.5960.1591-b

Vitamin B12 (cobalamin) has been cited prominently in the history of the Nobel Prizes, for its contributions to pernicious anemia, organic synthesis, and crystallography. Methylmalonyl-CoAmutase (MCM) is one of only two mammalian enzymes that rely on cobalamin, and Padovani and Banerjee describe the intricate mechanisms for ensuring that active cofactor is loaded onto MCM and inactive cofactor is removed. A trimeric adenosyltransferase (ATR) turns inactive cobalamin into the active AdoCbl form by adding the deoxyadenosine moiety derived from ATP. Only two of the three sites are occupied by AdoCbl molecules, and binding of the substrate ATP to the empty site is used to eject one AdoCbl in the fashion of a rotary motor. A second nucleotide-driven step is regulated by the G protein chaperone MeaB, which mediates a tripartite exchange between ATR and MCM; the binding energy of GTP is used to select in favor of the active AdoCbl versus cobalamin itself, and the hydrolysis energy of GTP is used to promote the release of inactive cofactor from MCM, which can occur during MCM turnover. Finally, a human mutation in MCM that has no effect on enzyme activity per se was shown to block the editing capacity of MeaB, providing a mechanistic explanation for methylmalonic aciduria in this patient.

Biochemistry48, 5350 (2009); Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.0908106106 (2009).

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