Pyrimidine biosynthesis

Abstract

Pyrimidines can be synthesized through either a de novo pathway from glutamine and bicarbonate or from uracil via a salvage pathway to form a common product, uridine 5‣ monophosphate. The six enzymes in the de novo pathway are carbamyl phosphate synthetase II, aspartate transcarbamylase, dihydroorotase, dihydroorotic acid dehydrogenase, orotate phosphoribosyl transferase, and orotidine 5′ phosphate decarboxylase. The first three (carbamyl phosphate synthetase, aspartate transcarbamylase, dihydroorotase) and last two enzymes (orotate phosphoribosyl transferase, orotidine 5′ phosphate decarboxylase) exist in separate multifunctional complexes. Both complexes tend largely to be cytoplasmic but may be linked to the membrane-bound enzyme (dihydroorotic acid dehydrogenase). The de novo biosynthesis of pyrimidines may be rate-limited at carbamyl phosphate synthetase and orotate phosphoribosyl transferase. Each complex is controlled by an activator phosphoribosyl pyrophosphate, in addition to product inhibitors, uridine 5′ monophosphate, or uridine 5′ triphosphate. Under normal conditions control is maintained by channeling carbamyl phosphate within the enzyme complex during its subsequent biochemical transformations. Such channeling is altered in hyperammonemic states wherein large quantities of carbamyl phosphate generated from the intramitochondrial ammonia-utilizing carbamyl phosphate synthetase I leak through the mitochondrial membrane to be converted to carbamyl aspartate via aspartate transcarbamylase and through sequential steps to form increased quantities of uridine 5′ monophosphate. The de novo pathway for pyrimidine biosynthesis is closely related to the de novo pathway for purine biosynthesis via common utilization of phosphoribosyl pyrophosphate as a substrate. Underutilization of phosphoribosyl pyrophosphate by the purine pathways as in the Lesch-Nyhan syndrome is accompanied by increased availability of this activator/substrate with consequent enhancement of de novo pyrimidine synthesis. The salvage pathway for pyrimidine biosynthesis converts uracil to uridine 5′ monophosphate, and is rate limited by uridine kinase which is inhibited by cytidine triphosphate. Pyrimidine biosynthesis in adult tissues is accomplished largely through the salvage pathway, while in tissues of the conceptus the de novo pathway predominates. Both pathways are increased in regenerating tissue or in the human lymphocyte undergoing blast transformation. Congenital disorders of pyrimidine biosynthesis are limited to the second enzyme complex in the de novo pathway. Hereditary orotic aciduria type I is consequent to a deficiency in orotate phosphoribosyl transferase and orotidine 5′ phosphate decarboxylase, and type II to a deficiency in orotidine 5′ phosphate decarboxylase. Both types respond to exogenous uridine. Studies in healthy subjects, treated with allopurinol to block orotidine 5′ phosphate decarboxylase, have indicated that purines and pyrimidines of dietary origin may have potential relevance for homeostatic regulation of pyrimidine biosynthesis.