A carbon-skeleton walk: a novel double rearrangement of glutaryl-CoA catalyzed by the human methylmalonyl-CoA mutase.

Methylmalonyl-CoA mutase is a member of the coenzyme B12-dependent family of isomerases and interconverts methylmalonyl-CoA and succinyl-CoA. We have examined the ability of the enzyme to effect a double rearrangement reaction when presented with glutaryl-CoA, a substrate analog with a three-carbon template on which two successive 1,2 migrations can occur. Our results demonstrate that the enzyme converts glutaryl-CoA to both methylsuccinyl-CoA and ethylmalonyl-CoA. To our knowledge, this is the first example of a double rearrangement reaction catalyzed by a coenzyme B12-dependent enzyme.