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Hepatic metabolism of 3‐hydroxypropionate, a toxic byproduct in propionic acidemia (590.2)

Propionic acidemia (PA) is a rare autosomal recessive disorder leading to inhibition of propionate entering an anaplerotic pathway, via propionyl‐CoA, of the citric acid cycle (CAC). PA is characterized by a defect in the conversion of propionyl‐CoA to methylmalonyl‐CoA through propionyl‐CoA carboxylase (PCC). Decreased activity of PCC shunts propionyl‐CoA into alternative metabolic pathways forming 3‐hydroxypropionate (3‐HPA), which increases in concentration to toxic levels. We investigated the metabolic fates of 3‐HPA in rat livers using the combination of metabolomics studies and mass isotopomer analysis. Isolated rat livers were perfused with recirculating buffer containing 2 mM (un)labeled 3‐HPA ([13C3] and [1‐13C]3‐HPA). Perfusate and liver tissue were analyzed via GC‐MS and LC‐MS/MS. 3‐HPA was shown to be converted to acetyl‐CoA, with loss of carbon‐1 from 3‐HPA rather than enter into the CAC anaplerotically via propionyl‐CoA. The proposed pathway of 3‐HPA conversion to malonyl‐CoA was disproven using [13C3] 3‐HPA labeling studies. Instead β‐alanine was labeled with further conversion to acetyl‐CoA proposed. The newly identified metabolic pathway of 3‐HPA in the rat liver may play important role in the detoxification of this compound.