INHIBITION OF THE GLYCINE CLEAVAGE SYSTEM BY BRANCHED-CHAIN AMINO-ACID METABOLITES

The effects of 18 normally occurring and 11 patalogical metabolites of the branched-chain amino acids on the glycine cleavage system were investigated on intact rat liver mitochondria. It was demonstrated, that 2-oxo-isovaleric acid, 2-methyl-butyric acid, and isobutyric acid significantly inhibited the glycine cleavage system in intact mitochondria. Further studies on the solubilized glycine cleavage system demonstrated that the inhibitory effect was due to 2-methyl-butyryl- CoA (linear noncompetitive inhibition, ki: 0.1-0.15 mM) and iso- butyryl-CoA (S-hyperbolic, I-linear noncompetitive inhibition, ki,: 0.2-0.3 mM). Both 2-methyl-butyric acid and isobutyric acid exhibited less inhibition (2-methyl-butyric acid: competitive inhibition, ki: 5.5 mM, isobutyric acid: competitive inhibition, ki 16 mM), while 2-oxo-isovaleric acid was without inhibitory effect, and probably affects intact mitochondria through transformation to isobutyryl-CoA. It is suggested that the inhibitory action of 2-methyl-butyryl- CoA and isobutyryl-CoA may explain the hyperglycinemia seen in propionyl-CoA carboxylase deficiency, methyl-malonyl-CoA mu- tase deficiency and β-ketothioIase deficiency. © 1979 International Pediatric Research Foundation, Inc.