Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias
Publication date: Available online 21 May 2019Source: Molecular Genetics and MetabolismAuthor(s): Stephen McCalley, David Pirman, Michelle Clasquin, Kendall Johnson, Shengfang Jin, Jerry VockleyAbstractBranched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of multiple enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). Three different acyl-CoA dehydrogenases (ACADs) are active in each catabolic pathway and genetic deficiencies in each have been identified. While characteristic metabolites related to the enzymatic block accumulate in each deficiency, for reasons that are not clear, clinical symptoms are only seen in the context of deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the leucine pathway. Metabolism of fibroblasts derived from patients with mutations in each of the BCAA ACADs were characterized using metabolomics to better understand the flux of BCAA through their respective pathways. Stable isotope labeled LEU, ILE, and VAL in patient and control cell lines revealed that mutations in isobutyryl-CoA dehydrogenase (IBDH in the valine pathway) lead to a significant increase in isobutyrylcarnitine (a surrogate for the enzyme substrate isobutyryl-CoA) leading to metabolism by short-branched chain acyl-CoA dehydrogenase (SBCADH in the isoleucine pathway) and production of the pathway end product propionylcarnitine (a surrogate for propi...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research