Mitochondrial malate dehydrogenase shows a complex regulation pattern in the presence of citrate. Previously published results indicate that this enzyme is activated by citrate in the NAD(+)----NADH direction and inhibited in the opposite direction. Moreover, high concentrations of L-malate or oxaloacetate produce deviations from the Michaelis-Menten behaviour. Results reported in this paper clearly show that citrate both activates and inhibits mitochondrial malate dehydrogenase in the same direction (NAD(+)----NADH), and in the same reaction medium, depending on substrate concentration. This surprising effect has made it necessary to propose a new kinetic mechanism that extends those previously suggested and allows us to explain both the citrate effect (activating or inhibitory) and the effect of high concentrations of L-malate and oxaloacetate.
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