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 B₁₂ into its active cofactor forms, and to deliver it to two known B₁₂-dependent enzymes. Herein, we report an unexpected strategy for cellular retention of B₁₂, an essential and reactive cofactor. If methylmalonyl-CoA mutase is unavailable to accept the coenzyme B₁₂ 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 B₁₂, 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 B₁₂ concentration in patients with dysfunctional methylmalonyl-CoA mutase but normal adenosyltransferase activity.