On the analysis of futile cycles in metabolism

Abstract

So-called futile cycles in cellular metabolism consist of paired opposing reactions that, if simultaneously operant, act only to degrade free energy of ATP to heat. Previous considerations of the behavior of such substrate cycles have indicated their possible usefulness in regulating flux along metabolic pathways, but such analyses have treated the cycles in isolation, i.e. without taking into account the effects of enzymatic inputs to and outputs from the cycle. We here develop models of three typical substrate cycles that include enzymatic inputs to and outputs from the cycle and allow the enzymes of the cycles per se to be subject to a variety of allosteric modulations. The non-linear equations which describe these models were solved by an iterative procedure for sets of parameter values of metabolic interest. The results, when analyzed using appropriate definitions of regulatory sensitivity and energetic futility, demonstrate that the effects of the enzymes leading into and out of the cycle may cause profound changes in the operation of the substrate cycle and therefore may not be ignored. We find that the structural differences among the three cycles considered here result in corresponding functional differences. Our results suggest that (1) the fructose-6-P/fructose-1,6-di-P cycle acts effectively to gate bidirectional flux, but doesn't appreciably enhance regulation of unidirectional flux, (2) the glucose/glucose-6-P cycle is well suited to perform a homeostatic function and to adjust the set points for these two metabolites, and (3) the cycle at the pyruvate crossroads functions largely as a complex switch box that directs metabolic flow towards gluconeogenesis or glycolysis not only in response to inputs of or requirements for oxaloacetate, pyruvate, and phosphoenolpyruvate, but also in response to the combined action of allosteric modulators on the individual enzymes of this substrate cycle.