Oxycyclopropyl radicals

Figure 24 A chemical model for the radical isomerization step in the action of MCM. Abstraction of bromine from 2-methyl-2-bromomethylmalonate diester by tributylsilyl radical generates the analogue of the substrate-related free radical in the action of MCM. The free radical rapidly undergoes isomerization to the 2-methylsuccinyl radical diester, which is quenched by tributylsilane. Radical isomerization presumably proceeds by way of the oxycyclopropyl radical.

The 5 -deoxyadenosyl radical from coenzyme B12 initiates the reaction by abstraction of hydrogen from the methyl group of methylmalonyl-CoA. The resultant free radical undergoes isomerization by internal cyclization to the oxycyclopropyl radical, which opens to the succinyl-CoA radical, as in the chemical counterpart of Figure 24. Hydrogen abstraction from the methyl group of 5 -deoxyadenosine completes the mechanistic cycle. 

This enzyme s role in humans is to assist the detoxification of propionate derived from the degradation of the amino acids methionine, threonine, valine, and isoleucine. Propionyl-CoA is carboxylated to (5 )-methylmalonyl-CoA, which is epimerized to the (i )-isomer. Coenzyme Bi2-dependent methylmalonyl-CoA mutase isomerizes the latter to succinyl-CoA (Fig. 2), which enters the Krebs cycle. Methylmalonyl-CoA mutase was the first coenzyme B -dependent enzyme to be characterized crystallographically (by Philip Evans and Peter Leadlay). A mechanism for the catalytic reaction based on ab initio molecular orbital calculations invoked a partial protonation of the oxygen atom of the substrate thioester carbonyl group that facilitated formation of an oxycyclopropyl intermediate, which connects the substrate-derived and product-related radicals (14). The partial protonation was supposed to be provided by the hydrogen bonding of this carbonyl to His 244, which was inferred from the crystal structure of the protein. The ability of the substrate and product radicals to interconvert even in the absence of the enzyme was demonstrated by model studies (15). 

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