B12 deficiency as a source of Acrylic acid in OAT
Summary
Itaconyl-CoA forms an adduct with Adenosylcobalamin, and this adduct inhibits MUT enzyme. This inhibition redirects Propionyl-CoA to the alternative pathway, which produces Acrylyl-CoA.
The accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the progression of steatosis to steatohepatitis with fibrosis.
Quotes
We detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate from the spontaneous reaction between the cysteine sulfhydryl group and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA.
Our results indicate MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that forms an adduct with adenosylcobalamin. This adduct in turn inhibits MUT activity and reduces Cbl levels.
Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment, which redirects propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway.
The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multihit progression of steatosis to steatohepatitis with fibrosis.
Elevated levels of acrylyl-CoA and 3-hydroxypropionate (3-HP), as well as their derivatives, are not normally detected at appreciable levels in healthy individuals (47).
Acrylyl-CoA and 3-HP typically accumulate following disruption of the canonical Cbl-dependent propionate catabolism pathway due to Cbl deficiency or mutations within propionyl-CoA carboxylase or MUT that affect enzyme activity (R1)
TCDD
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant that induces diverse biological and toxic effects, including reprogramming intermediate metabolism, mediated by the aryl hydrocarbon receptor.