title: Metabolic annotation of 2-ethylhydracrylic acid.
abstract: Increased levels of the organic acid, 2-ethylhydracrylic acid (2-EHA) occur in urine of subjects with impaired L(+)-isoleucine metabolism. Chiral intermediates formed during isoleucine degradation are (S) enantiomers. Blockage of (S) pathway flux drives racemization of (2S, 3S) L(+)-isoleucine and its (2S, 3R) stereoisomer, L(+)-alloisoleucine. This non-protein amino acid is metabolized to (R)-2-methylbutyryl CoA via enzymes common to branched chain amino acid degradation. Subsequently, (R) intermediates serve as alternate substrates for three valine metabolic enzymes, generating 2-EHA. Once formed, 2-EHA accumulates because it is poorly recognized by distal valine pathway enzymes. Thus, urinary 2-EHA represents a biomarker of isoleucine pathway defects. 2-EHA levels are also increased in rats exposed to the industrial solvent, ethylene glycol monomethyl ether or the neurotoxin precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In these cases, a block in (S) pathway isoleucine catabolism occurs at the level of (S)-2-methylbutyryl CoA conversion to tiglyl CoA via inhibition of electron transferring flavoprotein/ubiquinone oxidoreductase dependent reactions. Elevated urinary 2-EHA in propionyl CoA carboxylase deficiency and methylmalonic aciduria results from a buildup of distal intermediates in the (S) pathway of isoleucine degradation. In Barth syndrome and dilated cardiomyopathy with ataxia syndrome, 2-EHA is a byproduct of impeded propionyl CoA entry into the Krebs cycle.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA 94609,USA. Electronic address: rryan@chori.org.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
mesh_terms: D000818:Animals; D056889:Barth Syndrome / Q000378:metabolism; D006801:Humans; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000378:metabolism; D014631:Valerates / Q000378:metabolism*
chemical_list: D014631:Valerates; C007674:2-ethylhydracrylic acid
keywords: 2-Ethylydracrylic acid; Alloisoleucine; Barth syndrome; Dilated cardiomyopathy with ataxia syndrome; Isoleucine; Propionyl CoA carboxylase deficiency; Short/branched chain acyl CoA dehydrogenase; T2 thiolase; Valine