title: Inhibition of the glycine cleavage system by branched-chain amino acid metabolites.
abstract: 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 isobutyryl-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 mutase deficiency and beta-ketothiolase deficiency.
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000494:pharmacology*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D003065:Coenzyme A / Q000494:pharmacology; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014631:Valerates / Q000494:pharmacology
chemical_list: D000597:Amino Acids, Branched-Chain; D002087:Butyrates; D014631:Valerates; D003065:Coenzyme A; D005998:Glycine