Propionyl-CoA catabolism (propionate to succinyl-CoA via the methylmalonyl-CoA pathway)

The mitochondrial pathway that converts propionyl-CoA to succinyl-CoA, the anaplerotic route by which propionate carbon enters the TCA cycle. Propionyl-CoA arises from the catabolism of the branched-chain amino acids isoleucine and valine, of methionine and threonine, of odd-chain fatty acids, and of the cholesterol side chain (and from gut-microbial propionate). Three enzymatic steps: (1) the biotin-dependent propionyl-CoA carboxylase (PCC), an alpha6-beta6 dodecamer of PCCA (biotin-carboxylase / biotin-carboxyl-carrier alpha subunit) and PCCB (carboxyltransferase beta subunit), carboxylates propionyl-CoA to (2S)-methylmalonyl-CoA (D-methylmalonyl-CoA) using bicarbonate and ATP; (2) methylmalonyl-CoA epimerase (MCEE) racemises this to (2R)-methylmalonyl-CoA (L-methylmalonyl-CoA); and (3) the adenosylcobalamin (AdoCbl / vitamin B12)- dependent methylmalonyl-CoA mutase (MMUT) performs the carbon-skeleton rearrangement of L-methylmalonyl-CoA to succinyl-CoA. The mutase step depends on a dedicated cobalamin cofactor-supply system: MMAB (cblB) is the ATP:cob(I)alamin adenosyltransferase that synthesises AdoCbl, and MMAA (cblA) is a mitochondrial G3E-family GTPase that gates AdoCbl loading onto MMUT and protects/reactivates the holo-mutase. Inherited defects map cleanly onto the steps: PCCA/PCCB → propionic acidemia; MCEE → (usually mild) methylmalonic aciduria; MMUT → methylmalonic aciduria (mut type); MMAB → cblB and MMAA → cblA methylmalonic aciduria (both often vitamin-B12-responsive because they act on cofactor supply).