Metabolic resistance to tight-binding inhibitors of enzymes involved in the de novo pyrimidine pathway Simulation of time-dependent effects. Simulation of time-dependent effects

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Abstract
When a tight-binding inhibitor interacts with a target enzyme of a metabolic pathway, the end products of the pathway are depleted and the substrate(s) for the inhibited reaction accumulate. The accumulating substrate(s) can reach a concentration which is sufficiently high that the inhibition is effectively reversed, with restoration of the original flux through the inhibited reaction. A theoretical model was developed for this phenomenon which were called metabolic resistance. The technique of numerical integration was successfully used to simulate the effects of inhibition of several enzymes in the pathway of pyrimidine biosynthesis. Utilizing appropriate dissociation constants and enzyme concentrations for the inhibited systems, these simulations are consistent with published experimental data for the interactions of N-phosphonacetyl-L-aspartate (PAcAsp) with mammalian aspartate transcarbamoylase in vitro and of 5-fluorodeoxyuridine-5''-phosphate (FdUMP) with thymidylate synthetase in vivo. A simulation is presented of the expected effects in vivo of phosphoribofuranosylbarbituric acid (BMP), a tight-binding inhibitor of OMP decarboxylase. On addition of BMP, there is a sequential depletion of all pyrimidine intermediates between UMP and dCDP and a concomitant accumulation of OMP [2-methyl-4-amino-5-hydroxymethylpyrimidine]. OMP reaches a new steady-state concentration and the concentrations of the depleted intermediates rise to their original levels. The depletion of dCDP at various concentrations of BMP was simulated; since dCDP is committed to DNA synthsis the dCDP concentrations can be integrated over time to calculate the amount of DNA synthesis and thereby predict the delay in cell division which would be elicited by BMP. This form of analysis may help to explain in quantitative terms why inhibitors of nucleic acid biosynthesis have a selective toxicity for rapidly growing tumor cells.

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