Sacrificial Cobalt-Carbon Bond Homolysis in Coenzyme B12 as a Cofactor Conservation Strategy

A sophisticated intracellular trafficking pathway in humans is used to tailor vitamin B-12 into its active cofactor forms, and to deliver it to two known B-12-dependent enzymes. Herein, we report an unexpected strategy for cellular retention of B-12, an essential and reactive cofactor. If methylmalonyl-CoA mutase is unavailable to accept the coenzyme B-12 product of adenosyltransferase, the latter catalyzes homolytic scission of the cobalt-carbon bond in an unconventional reversal of the nucleophilic displacement reaction that was used to make it. The resulting homolysis product binds more tightly to adenosyltransferase than does coenzyme B-12, facilitating cofactor retention. We have trapped, and characterized spectroscopically, an intermediate in which the cobalt-carbon bond is weakened prior to being broken. The physiological relevance of this sacrificial catalytic activity for cofactor retention is supported by the significantly lower coenzyme B-12 concentration in patients with dysfunctional methylmalonyl-CoA mutase but normal adenosyltransferase activity.