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...