Mammalian methylmalonate-semialdehyde dehydrogenase

Abstract

Methylmalonate-semialdehyde dehydrogenase (MMSDH), located in the mitochondrial matrix space, catalyzes the irreversible oxidative decarboxylation of malonate semialdehyde and methylmalonate semialdehyde to acetyl-CoA and propionyl-CoA, respectively. These reactions are in the distal portions of the valine and pyrimidine catabolic pathways. 1,2 MMSDH belongs to the aldehyde dehydrogenase superfamily,3,4 but is unique among the members of this family because coenzyme A is required for the reaction and a CoA ester is produced.1,2 MMSDH, like other aldehyde dehydrogenases, has esterase activity.5 An active site S-acyl enzyme is common to both the esterase reaction and the aldehyde dehydrogenase/CoA ester synthetic reaction.5 An active site cysteine residue (Cys-285 in rat MMSDH3) is acetylated during hydrolysis of p-nitrophenyl acetate by MMSDH. Acetyl-CoA is produced instead of acetate from p-nitrophenyl acetate when the reaction is conducted in the presence of coenzyme A.5 Long-chain fatty acyl-CoA esters also inactivate MMSDH by acylation of its active site cysteine residue,6 presumably by reversal of the above process. Active site acylation has been proposed as a mechanism for the regulation of MMSDH activity in vivo by long-chain fatty acids.7