Effect of Valine on Propionate Metabolism in Control and Hyperglycinemic Fibroblasts and in Rat Liver

Abstract

Fibroblastspropionyl-CoA carboxylase methylmalonic acidemia r a t liver methylmalonyl-CoA m u t a s e valine nonketotic hyperglycinemia Effect of Valine on Propionate Metabolism in Control and Hyperglycinemic Fibroblasts and in Rat Liver B E l T Y REVSIN,'36' JOYCE LEBOWITZ, AND GRANT MORROW I11Deparrrtlenr of Pediarrics, Uttiversity of Arizona College of Medicine, Arizona Medical Center, Tucson, Arizona, USA Summary propionic acidemia (3), and isovaleric acidemia (2), whereasMeasurement of methylmalonyl-CoA mutase and propionylCoA carboxylase activities in lysates from fibroblasts derived from control, nonketotic hyperglycinemia, propionic acidemia, and both vitamin B,,-responsive and -nonresponsive variants of methylmalonic acidemia showed only one abnormality: a 59% decrease in carboxylase activity in the nonketotic hyperglycinemic lysates ( P < 0.01). When fibroblasts from all cell types were grown on valine-supplemented (24 mM) media, mutase activity was generally inhibited. A s for carboxylase activity, control lines were inhibited 35% as compared to controls without valine and propionic acidemia activity was undetectable. On the other hand, carboxylase activity in both methylmalonic acidemia variants was increased 40% and nonketotic hyperglycinemia carboxylase activity was increased 80% ( P < 0.01) when grown on valine-supplemented media. Isoleucine could not substitute for valine in producing increased carboxylase activity in these mutants.Glycine cleavage activity in fresh rat liver homogenates (11.1 pmollmg protein/90 min) did not vary significantly when 2 4 mM valine was added to the reaction (9.9 pmollmg protein/90 min). Therefore, the hyperglycinemia observed in both ketotic and nonketotic forms is probably not caused by a direct effect of valine on the glycine cleavage reaction.These data suggest that the presence of increased amounts of propionic acid in serum or urine does not necessarily rule out the possibility of nonketotic hyperglycinemia due to the decreased activity of the carboxylase enzyme. Speculation others exhibit no ketbsis, e.g., nonketotic hyperglycinemia (4). Those hyperglycinemic states associated with ketosis appear to be diseases which result from primary enzyme defects either in the propionate pathway (3, 21) or in one of the catabolic pathways of branched chain amino metabolism (2, 14). A s a result, the hyperglycinemia appears to be a secondary phenomena. In nonketotic hyperglycinemia (NKH), it has been suggested that the primary defect causes hyperglycinernia and results from decreased activity of the glycine cleavage reaction (26, 34). However, recent studies have demonstrated diminished glycine cleavage activity in the ketotic forms of hyperglycinemia as well as in the nonketotic form (25, 32). These latter observations suggest that the decreased glycine cleavage activity found in the NKH syndrome may be a secondary phenomena possibly due to mechanisms similar to those seen in the ketotic states.Studies from our own laboratory have demonstrated that fibroblasts derived fro...

Propionyl-CoA carboxylase – A review

“…Propionyl-CoA is produced by catabolism of c holesterol, v aline, o dd chain fatty acids, m ethionine, i soleucine and t hreonine (c-VOMIT) [2, 16–18]. Like other carboxylases, PCC is promiscuous and can carboxylate several other acyl-CoAs, but has greatest affinity for propionyl-CoA (Km = 0.29 mM).…”

Biochemical Aspects of Transmission at Inhibitory Synapses: The Role of Glycine

“…The nonketotic syndrome was originally thought to be present only with the defect in oxidation of glycine and without altered propionic or methylmalonic acid metabolism (Baumgartner and Wick, 1972;Baumgartner et at., 1975). However, more recent reports have provided evidence for other metabolic defects associated with the nonketotic syndrome (Wada et at., 1972;Krieger and Hart, 1974;Corbeel et aI., 1975;De Groot et at., 1975;Geison et aI., 1975;Farriaux et aI., 1976;Kolvraa et aI., 1976;Revsin et at., 1977).…”

Defective glycine cleavage system in nonketotic hyperglycinemia. Occurrence of a less active glycine decarboxylase and an abnormal aminomethyl carrier protein.

“…It may be relevant that Revsin et al. (35), reported a 59% decrease in the activity of propionyl-CoA carboxylase in lysates of fibroblasts derived from a patient with nonketotic hyperglycinemia, and Stumpfet al (36) showed that propionyl-CoA is a potent inhibitor of succinylCoA ligase; half-maximal inhibition occurred at 0.2 mM propionyl-CoA. In any case the observed reduction in the activity of the P-protein does not appear to be an artifact of storage of the liver.…”