1. Normal human urine contains small amounts (< 4 mg/g of creatinine) of 2-ethylhydracrylic acid, formed, we 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 methyl malonate. 6. Valine metabolites do not interact with the R-isoleucine pathway under the conditions of these experiments in vivo.
Demonstration of a new mammalian isoleucine catabolic pathway yielding an R series of metabolites
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O A Mamer, S S Tjoa, C R Scriver, G A Klassen; Demonstration of a new mammalian isoleucine catabolic pathway yielding an R series of metabolites. Biochem J 15 December 1976; 160 (3): 417–426. doi: https://doi.org/10.1042/bj1600417a
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