A Review: Biological and Clinical Aspects of Pyrimidine Metabolism

Abstract

Interest in pyrimidine nucleotide biosynthesis has stemmed largely from the importance of these molecules as components of nucleic acids. Regulation of pyrimidine biosynthesis has been most extensively investigated in micro-organisms in which cell division is effectively controlled by regulation of the activity of the enzymes of the d e n o v o pathway (77, 11 0). The relation between pyrimidine biosynthesis and cellular proliferation in mammals has become clearer with the accumulation of a considerable body of evidence which indicates that there is a close correlation between the activity of enzymes involved in pyrimidine biosynthesis and the rate of cellular proliferation.The d e n o v o pyrimidine biosynthetic pathway and the urea cycle b o t h utilize carbamyl phosphate, and important nitrogen carrier. The biosynthesis of pyrimidine and purine nucleotides are connected by a common intermediate, phosphoribosyl pyrophosphate (PRPP). In addition, pyrimidine nucleotides act as sugar and phospholipid carriers and are important in lipopolysaccharide biosynthesis. The importance of these interrelations is most forcibly emphasized b y certain clinical phenomena which will be discussed later. This paper will attempt t o review the broad biologic aspects of pyrimidine nucleotide biosynthesis. A detailed consideration of d e n o v o pyrimidine biosynthesis in eucaryotic cells is available in the recent review by Jones (81). Pyrimidine biosynthesis in procaryotes has been reviewed in depth by O'Donovan and Neuhard (1 10). PATHWAYS O F PYRIMIDINE NUCLEOTIDE BIOSYNTHESISIn cells from multicellular organisms, pyrimidine nucleotide biosynthesis can proceed b y two mechanisms. D e n o v o biosynthesis of uridylic acid proceeds from simple components such as carbon dioxide, a source of nitrogen (either ammonia or the amide nitrogen of glutamine), ATP, aspartate. and ribose in the form of phosphoribosyl p y r~p h o s~h a t e . A reutilization ("salvage") mechanism is also available t o cells.-.whereby preformed pyrimidine bases o r nucleosides can be converted t o the nucleotide by the addition of ribose phosphate or phosphate. DE NOVO MECHANISMD e n o v o biosynthesis of uridylic acid required six enzymatic steps (Fig. 1). In procaryotes one enzyme supplies the carbamyl phosphate required for both pyrimidine nucleotide and arginine biosynthesis. Consequently, aspartate transcarbamylase is the first enzyme unique to the d e n o v o pyrimidine pathway and an important locus for control of the pathway (77).In contrast, in ureotelic vertebrates, there are t w o carbamyl phosphate synthetases. The first, carbamyl phosphate synthetase I, is located in the inner membrane of the mitochondrion of the liver and also appears t o be present in small quantities in kidney and small intestine (82). The second, carbamyl phosphate syntlietase 11, has a more ubiquitous distribution and was first demonstrated t o be present in Ehrlich ascites cells (58,59) and in hematopoietic mouse spleen (75,143). This enzyme was originally difficult t o dete...

Urinary purines and pyrimidines in patients with hyperammonemia of various origins

“…CPS I provides carbamylphosphate (CP) for the urea cycle and CPS II for pyrimidine biosynthesis [39]. However, at least in rat liver, the two CPpools are not completely separated [40] and the mitochondrial CPS contributes to hepatic pyrimidine synthesis [ 411.…”

Effect of uridine on cellular UTP and glycogen synthesis in skeletal muscle: stimulation of UTP formation by insulin.

“…However, uracil nucleotides serve also as intermediates in the formation of glycoproteins of cell membranes (17,18) so that an effect of insulin on UTP synthesis could lead to alterations in the properties of cellular membranes. If insulin also influences the metabolism of cytosine nucleotides, such an action of the hormone could be involved in the effect of insulin on the synthesis of phospholipids (19).…”

Pyrimidine Metabolism during Restorative Brain Growth after Neonatal Undernutrition in the Rat

“…Recent evidence has accumulated indicating that there is a close correlation between the activity of enzymes involved in pyrimidine biosynthesis and the rate of cellular proliferation in mammals (10). Such incorporation of pyrimidines into nucleic acids involves a de novo pathway which uses the simple substrates C o p , ATP, and glutamine and leads to the formation of uridylic acid (10).…”

“…Such incorporation of pyrimidines into nucleic acids involves a de novo pathway which uses the simple substrates C o p , ATP, and glutamine and leads to the formation of uridylic acid (10). Additionally, "salvage pathway" or reutilization pathway enzymes may incorporate pyrimidine nucleosides from exogenous sources or from endogenous breakdown of nucleic acids.…”

“…Additionally, "salvage pathway" or reutilization pathway enzymes may incorporate pyrimidine nucleosides from exogenous sources or from endogenous breakdown of nucleic acids. Furthermore, uridylic acid may be converted into a range of pyrimidine nucleotides by a series of interconversion enzymes, many of which appear to be under complex metabolic control (10) The rat cerebellum, which develops almost totally within the first 3 postnatal weeks and undergoes an 8-10-fold increase in DNA content during that period, has been used in our laboratory as a model to study cell division in general as well as to study cell division in an organ whose cells are mostly microneuron precursors.…”