The effects of 18 normally occurring and 11 patalogical metabolites of the branchcd-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 ß-ketothiolase deficiency.
Speculation In patients not suffering from any known inborn error of metabolism, hyperglycinemia has been described in connection with two circumstances, namely, severe generalized illness and medication with dipropylacetic acid. Because both these conditions might cause some derangement of the branched-chain amino acid metabolism, it is speculated that this hyperglycinemia might be due to inhibition of the glycine cleavage system by 2-methyl-butyryl-CoA and isobutyryl-CoA, and that these conditions thus might serve as models for ketotic hyperglycinemia.