title: Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria.
abstract: 2-Methylcitrate was tested in vitro on enzymes which interact with citrate and isocitrate. It was found to inhibit citrate synthase, aconitase, the NAD+- and NADP+-linked isocitrate dehydrogenase. This inhibition was competitive in nature except in the case of aconitase, and the Ki for all the enzymes was in the range of 1.5-7.6 mM. Phosphofructokinase was also inhibited by 2-methylcitrate with 50% inhibition achieved at 1 mM. ATP-citrate lyase and acetyl-CoA carboxylase were not inhibited by this compound. 2-Methylcitrate was not a substrate for ATP-citrate lyase. Acetyl-CoA carboxylase was activated by 2-methylcitrate with a Ka of 2.8 mM. The apparent Km (3.3 mM) for 2-methylcitrate for the mitochondrial citrate transporter was about 10-fold higher than the apparent Km (0.26 mM) for citrate. The tricarboxylase carrier can also be inhibited by low concentrations (0.2 mM) of 2-methylcitrate when the concentration of citrate is close to the apparent Km. Accumulation of 2-methylcitrate inside the mitochondrion, therefore, might lead to inhibition of enzymes in the citric acid cycle and thereby contribute to the ketogenesis and hypoglycemia seen under these conditions.
mesh_terms: D000818:Animals; D002951:Citrates / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D008314:Malonates / Q000652:urine*; D008764:Methylmalonic Acid / Q000652:urine*; D008930:Mitochondria, Liver / Q000201:enzymology; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D011422:Propionates / Q000097:blood*; D051381:Rats
chemical_list: D002951:Citrates; D008314:Malonates; D011422:Propionates; D008764:Methylmalonic Acid; D010732:Phosphofructokinase-1