Demonstration of a new mammalian isoleucine catabolic pathway yielding an R series of metabolites

1. Normal human urine contains small amounts (less than 4 mg/g of creatinine) of 2 ethylhydracrylic acid, formed, the authors believe, by a previously undisclosed endogenous catabolic pathway for the oxidation of a newly described series of R metabolites of isoleucine. 2. Urinary excretion of 2 ethylhydracrylic acid is variably increased in defects of isoleucine oxidation at distal steps in the catabolic pathway (3 oxoacyl CoA thiolase deficiency and methylmalonyl CoA mutase deficiency) and is diminished when proximal steps of the oxidative pathway are blocked as in branched chain oxo acid decarboxylase deficiency ('maple syrup urine' disease). 3. Precursors of R pathway metabolites [R(-) 2 methylbutyrate and 2 ethylacrylate] lead to increased 2 ethylhydracrylate excretion in the mammal (rat, rabbit and dog); the corresponding S metabolites [S(+) 2 methylbutyric acid and tiglic acid], when given in equimolar amounts, have little effect on its excretion, suggesting that little or no interconversion between S and R metabolites occurs in vivo. 4. Studies with ²H labelled precursors indicate that conversion of R 2 methylbutyrate into 2 ethylhydracrylic acid occurs by a direct pathway (apparently via 2 ethylacrylic acid). 5. The further oxidation of 2 ethylhydracrylic acid to ethylmalonic acid was demonstrated, and may be analogous to S metabolite oxidation via methylmalonate. 6. Valine metabolites do not interact with the R isoleucine pathway under the conditions of these experiments in vivo.