Specificity of the transport system for tricarboxylic acid cycle intermediates in renal brush borders

Uptake studies employing renal brush border membranes were used to examine the structural specificity of the TCA cycle intermediate transport system. The kinetics of reciprocal inhibition between succinate and citrate revealed these compounds to be transported by a common mechanism. The Michaelis constant for succinate (0.11 mm) was significantly lower than that of citrate (0.28 mm), indicating that the system has a higher affinity for succinate than for citrate. The specificity of the transport system was determined from the relative inhibitory constants of 40 organic acids on the transport of succinate. The results established that the system is highly specific for 4-carbon, terminal dicarboxylic acids in the trans-configuration, including the major intermediates of the TCA cycle. The system is comparatively insensitive to monocarboxylates. Substitution of one of several polar, noncharged residues on the α-carbon of succinate permitted interaction of the substrate with the transport system, but substitutions on both the α and \-carbons did not. The structural specificity of the system is fundamentally different from that of the dicarboxylate and tricarboxylate exchange systems of mitochondria. The role of this transport system in the reabsorption of TCA cycle intermediates from the proximal tubule is discussed.