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Biological and Clinical Aspects of Pyrimidine Metabolism

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Biological and Clinical Aspects of Pyrimidine Metabolism Pediat. Res. 8: 724-734 (1 974) A Review: Biological and Clinical Aspects of Pyrimidine Metabolism RODNEY L. LEVINE, NICHOLAS J. HOOGENRAAD, AND NORMAN KRETCHMER(' ) Division of Developmental Biology, Department of Pediatrics, Stanford University Medial Center, Stanford, California, USA Interest in pyrimidine nucleotide biosynthesis has stemmed or the amide nitrogen of glutamine), ATP, aspartate. and largely from the importance of these molecules as components ribose in the form of phosphoribosyl pyr~phos~hate.A of nucleic acids. Regulation of pyrimidine biosynthesis has reutilization ("salvage")-. mechanism is also available to cells. been most extensively investigated in micro-organisms in whereby preformed pyrimidine bases or nucleosides can be which cell division is effectively controlled by regulation of converted to the nucleotide by the addition of ribose the activity of the enzymes of the de novo pathway (77, 11 0). phosphate or phosphate. The relation between pyrimidine biosynthesis and cellular proliferation in mammals has become clearer with the DE NOVO MECHANISM accumulation of a considerable body of evidence which indicates that there is a close correlation between the activity De novo biosynthesis of uridylic acid required six enzymatic of enzymes involved in pyrimidine biosynthesis and the rate of steps (Fig. 1). In procaryotes one enzyme supplies the cellular proliferation. carbamyl phosphate required for both pyrimidine nucleotide The de novo pyrimidine biosynthetic pathway and the urea and arginine biosynthesis. Consequently, aspartate trans- cycle both utilize carbamyl phosphate, and important nitrogen carbamylase is the first enzyme unique to the de novo carrier. The biosynthesis of pyrimidine and purine nucleotides pyrimidine pathway and an important locus for control of the are connected by a common intermediate, phosphoribosyl pathway (77). pyrophosphate (PRPP). In addition, pyrimidine nucleotides In contrast, in ureotelic vertebrates, there are two carbamyl act as sugar and phospholipid carriers and are important in phosphate synthetases. The first, carbamyl phosphate synthe- lipopolysaccharide biosynthesis. The importance of these tase I, is located in the inner membrane of the mitochondrion interrelations is most forcibly emphasized by certain clinical of the liver and also appears to be present in small quantities in phenomena which will be discussed later. kidney and small intestine (82). The second, carbamyl This paper will attempt to review the broad biologic aspects phosphate syntlietase 11, has a more ubiquitous distribution of pyrimidine nucleotide biosynthesis. A detailed considera- and was first demonstrated to be present in Ehrlich ascites tion of de novo pyrimidine biosynthesis in eucaryotic cells is cells (58, 59) and in hematopoietic mouse spleen (75, 143). available in the recent review by Jones (81). Pyrimidine This enzyme was originally difficult to detect because of its biosynthesis in procaryotes has been reviewed in depth by relatively low activity and high lability. However, the O'Donovan and Neuhard (1 10). discovery that the enzyme could be stabilized by its substrate, magnesium-ATP (59), and by dimethyl sulfoxide and glycerol PATHWAYS OF PYRIMIDINE NUCLEOTIDE BIOSYNTHESIS (144, 146), made it possible to demonstrate that the enzyme was widely distributed in mammalian tissues (74, 128, 144, In cells from multicellular organisms, pyrimidine nucleotide 163). biosynthesis can proceed by two mechanisms. De novo The two synthetases have different properties which lends biosynthesis of uridylic acid proceeds from simple components support to the concept that they have distinct roles in such as carbon dioxide, a source of nitrogen (either ammonia supplying carbamyl phosphate for either arginine biosynthesis CO, + Mg-ATP + GLUTAMINE c0i$2+-:e+ CARBAMYL- P ASPARTATE tronscorbamylose DIHYDRpOROTATE. dihydroytoseCARBAMYLASPARTATE orotate phosphoribosyl tronsferose r OROTIDINE MONOPHOSPHATE I / \* PRPP 2 Pi orotidylate decorboxy lose 4 UMP Fig. 1. Pathway for de novo biosynthesis of pyrimidine nucleotides in eucaryotic cells. PRPP: phosphoribosyl pyrophosphate. 7 24 PYRIMIDINE METABOLISM 725 or for uridylic acid biosynthesis (80). The mitochondria1 be effectively channeled into de novo pyrimidine biosynthesis carbamyl phosphate synthetase I can utilize ammonia as a (36, 80). source of nitrogen and is activated by N-acetyl glutamate, It has become evident recently that the conversion of which also stimulates urea biosynthesis in liver slices. orotate to uridylate may be an important site of regulation in Carbamyl phosphate synthetase 11, found in the cytosol, de novo pyrimidine biosynthesis. Uridine substantially inhibits utilizes glutamine as its normal nitrogen source as indicated by the incorporation of (' c)aspartate (1 17) and ' ~0~ (70) the K, values for glutamine and ammonia (144). In addition, into uridine nucleotides in hepatoma cells. Hoogenraad and glutamine analogs inhibit this enzyme but do not affect Lee (70) showed that the effects of uridine were caused by an carbamyl phosphate synthetase I (59, 60, 163). The role of effect on the level of activity of orotate phosphoribosyl carbamyl phosphate synthetase I1 in de novo pyrimidine transferase, even though uridine or its nucleotides did not biosynthesis is indicated, not only by its general distribution in directly inhibit this enzyme. In addition, it appears that the most tissues, but also by the factors that control its activity. availability of PRPP may be crucial in the regulation of de UTP, an end product of the de novo pyrimidine pathway, is a novo pyrimidine biosynthesis, inasmuch as orotate accumu- feedback inhibitor of carbamyl phosphate synthetase I1 (74, lates in cultures of mammalian cells to which small amounts of 94, 143), apparently acting in an allosteric fashion (94). adenine have been added (73), and the toxic effects of adenine Phosphoribosyl pyrophosphate, a substrate required for both (73, 102) may be removed by supplementation of cells with purine and pyrimidine biosynthesis, enhances the activity of uridine (73), showing that the toxicity is caused by pyrimidine carbamyl phosphate synthetase I1 when added at low starvation. concentrations (132, 145, 147). The activity of orotidylate decarboxylase also can be The second enzyme of the do novo pathway is aspartate regulated by the pyrimidine nucleotides, UMP and CMP (3, 15, transcarbamylase (EC. 2.1.3.2). In fungi this enzyme is part of 16, 33). However, it is doubtful that this is an important a multifunctional complex which also contains carbamyl regulatory mechanism, because the Ki for inhibition by these phosphate synthetase I1 (8 1). These two enzymes are also in nucleotides is high and the levels of UMP and CMP are usually close physical association in mammalian tissues (71, 80). In extremely low (3, 1 17). addition, Shoaf and Jones (130-132) found that the third enzyme of the de novo pyrimidine pathway, dihydroorotase REUTILIZATION OF PYRIMIDINE NUCLEOSIDES (EC. 3.5.2.3), is also present in the complex. Pyrimidine nucleosides from exogenous sources and from The aspartate transcarbamylase activity of the mammalian endogenous breakdown of nucleic acids are available for complex, unlike the enzyme from many procaryotic species pyrimidine nucleotide biosynthesis through the mediation of a and yeast, is not sensitive to feedback regulation by number of enzymes which have collectively been called the nucleotides (35, 7 1, 120). "salvage pathway" or "reutilization pathway." The enzymes Dihydro-orotase activity is only marginally affected by of this pathway (Fig. 2) found in mammalian tissues are pyrimidine compounds, with the exception of orotic acid, uridine phosphorylase (EC. 2.4.2.3), uridine kinase (EC. which substantially inhibits the enzyme (19, 58). Dihydro- 2.7.1.48), and thymidine kinase (EC. 2.4.2.4). orotic acid dehydrogenase (EC. 1.3.3.1), the next enzyme in Uridine phosphorylase catalyzes reversibly the reaction the pathway, is possibly the least studied of the de novo between uracil and ribose 1-phosphate to form uridine and pyrimidine enzymes. The electron acceptor for the conversion inorganic phosphate. The enzyme is widely distributed in ani- of dihydro-orotic acid to orotic acid has not been character- mal tissues (23, 86). Uridine kinase catalyzes the conversion ized for the mammalian enzyme. This enzyme is apparently of uridine to UMP. The name is somewhat limiting because the associated with the cell membranes since Shoaf and Jones enzyme will also convert cytidine to CMP (134). Uridine (132) showed that, in contrast to the other enzymes required kinase is required for the conversion of the antineoplastic for de novo pyrimidine nucleotide biosynthesis, the majority agent 5-fluorouracil to the active nucleotide, and resistance to of the dihydro-orotate dehydrogenase activity from Ehrlich this drug occurs when the enzyme becomes modified (135). In ascites cells sediments with the nuclei and cell membrane the sequence of reactions leading from uridine to UTP, the fraction. The terminal two enzymes of the de novo pyrimidine conversion of uridine to UMP is rate limiting and sensitive to inhibition by UTP and CTP (1). The phosphorylation of pathway also exist as a complex in mammals. Appel (2) found that orotate phosphoribosyl transferase and orotidylate de- cytidine is also inhibited by UTP and CTP. carboxylase copurified when these enzymes were isolated from Thymidine kinase is also widely distributed in animal tissues as evidenced by the
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