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

• DOI: 10.1096/fasebj.28.1_supplement.590.2
• Publication Date: 2021-06-16T10:00:02Z
• Authors: Kirkland Wilson; Yong Han; John Koshy; Henri Brunengraber; Gregory Tochtrop; Guofang Zhang
• Keywords: Propionic acidemia; Isotopomers; Metabolic pathway; Tricarboxylic acid

Propionic acidemia (PA) is a rare autosomal recessive disorder leading to inhibition of propionate entering an anaplerotic pathway, via propionyl‐CoA, the citric acid cycle (CAC). PA characterized by defect in conversion propionyl‐CoA methylmalonyl‐CoA through carboxylase (PCC). Decreased activity PCC shunts into alternative metabolic pathways forming 3‐hydroxypropionate (3‐HPA), which increases concentration toxic levels. We investigated fates 3‐HPA rat livers using combination metabolomics studies and mass isotopomer analysis. Isolated were perfused with recirculating buffer containing 2 mM (un)labeled ([ 13 C 3 ] [1‐ C]3‐HPA). Perfusate liver tissue analyzed GC‐MS LC‐MS/MS. was shown be converted acetyl‐CoA, loss carbon‐1 from rather than enter CAC anaplerotically propionyl‐CoA. The proposed pathway malonyl‐CoA disproven [ labeling studies. Instead β‐alanine labeled further acetyl‐CoA proposed. newly identified may play important role detoxification this compound. Grant Funding Source : Supported CRTP T32 Training