Physiological concentrations of 2-oxoglutarate regulate the activity of phosphoenolpyruvate carboxykinase in liver.
2-Oxoglutarate was found to inhibit purified rat liver phosphoenolpyruvate carboxykinase when the assay was performed in the direction of either phosphoenolpyruvate or oxaloacetate synthesis. The inhibition was competitive with respect to oxaloacetate or phosphoenolpyruvate, the Ki values being 0.32 +/- 0.04 mM 0.63 +/- 0.19 mM respectively. 2-Oxoglutarate inhibited non-competitively when tested against GTP or Mn2+. The reported cytosolic concentrations of 2-oxoglutarate in rat hepatocytes are such that the enzyme is likely to be significantly inhibited under basal conditions. The cytosolic concentration of 2-oxoglutarate is known to fall precipitously under the influence of glucagon and other hormones that stimulate gluconeogenesis, and it is suggested that the hormone-induced decrease in 2-oxoglutarate content would alleviate the inhibition of phosphoenolpyruvate carboxykinase and stimulate flux from oxaloacetate to phosphoenolpyruvate. The implications of this finding to the rationalization of the role of pyruvate kinase in the stimulation of gluconeogenesis in the fasted state are discussed.
Titheradge
M A
MA
School of Biological Sciences, University of Sussex, Falmer, Brighton, U.K.
Picking
R A
RA
Haynes
R C
RC
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D006160:Guanosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007656:Ketoglutaric Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology*; D008291:Malate Dehydrogenase / Q000037:antagonists & inhibitors; D008297:Male; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology; D010071:Oxaloacetates / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D007656:Ketoglutaric Acids; D010071:Oxaloacetates; D008345:Manganese; D006160:Guanosine Triphosphate; D008291:Malate Dehydrogenase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)