Abstract
Dividing cells require adequate amounts of purine and pyrimidine nucleotides for nucleic acid synthesis. The de novo pathway of pyrimidine biosynthesis is regulated to meet these growth requirements. In mammalian tissues the first enzyme in the patheway, carbamoyl phosphate synthesis (CPS), is inhibited by the pyrimidine nucleotide UTP. This inhibition may effectively limit de novo pyrimidine synthesis since cps activity is the limiting enzyme for the pathway.
A detailed study of the kinetics of UTP inhibition provides support for the hypothesis that regulation of CPS is the physiological mechanism for control of the de novo pathway. CPS gives a sigmodial velocity curve when the substrate ATP is varied in the absence of UTP. The curve fits a 2/1 function which suggests that ATP stimualtes activity by acting both as a homotropic substract and as an allosteric effector. UTP inhibits by competition with ATP and increases the sigmoidality of the curve. The K1 for UTP is 35 μM. The kintetic constants (Km for ATP = 3 mM) are such that CPS should be extremely sensitive to deviations from the normal cellular concentrations of ATP and UTP.
The purine nucleotide ATP stimulates CPS while the pyrimidine nucleotide UTP inhibits so that precursors of nucleic acid interact on the enzyme. Thus CPS may play a pivotal role in the regulation of cellular proliferation. These findings might explain the observation that uridine greatly reduces urinary excretion of orotic acid in children with hereditary orotic aciduria. This action further supports the concept that regulation of CPS is a physiologically important control mechanism.
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Levine, R., Hoogenraad, N. & Kretchmer, N. Regulation of cellular growth: Control of pyrimidine biosynthesis. Pediatr Res 5, 418 (1971). https://doi.org/10.1203/00006450-197108000-00197
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DOI: https://doi.org/10.1203/00006450-197108000-00197