Uridine monophosphate pyrimidine synthesis

The major intermediates in the biosynthesis of nucleic acid components are the mononucleotides uridine monophosphate (UMP) in the pyrimidine series and inosine monophosphate (IMP, base hypoxanthine) in the purines. The synthetic pathways for pyrimidines and purines are fundamentally different. For the pyrimidines, the pyrimidine ring is first constructed and then linked to ribose 5 -phosphate to form a nucleotide. By contrast, synthesis of the purines starts directly from ribose 5 -phosphate. The ring is then built up step by step on this carrier molecule. 

Thymidine triphosphate (TTP) depletion. AZT and thymidine (T) compete with each other for phosphorylation by thymidine kinase into AZT-monophosphate (AZT-MP) and thymidine-monophosphate (TMP), respectively (Fig. 13) (Lynx and McKee 2006). AZT can therefore decrease the formation of TMP and TTP, whose relative deficiency can then slow mtDNA replication (Lynx and McKee 2006). Interestingly the administratimi of uridine in animals and perhaps also in humans can prevent AZT, ddC, and d4T toxicity (Walker and Venhoff 2005 Banasch et al. 2006). Uridine administration may provide an alternate route for TTP synthesis, thus preventing TTP depletimi and the impairment of mtDNA replication (Lynx and McKee 2006). Furthermore, the uridine-induced restoration of mtDNA levels and respiratory chain functirm could improve the activity of dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in pyrimidine synthesis. Thus, a virtuous circle is initiated by uridine supplementation (Setzer et al. 2008). 

Fig. 23.1. Pyrimidine pathways Pathways for the de novo synthesis, interconversion, and breakdown of pyrimidine ribonucleotides, indicating their metabolic importance as the essential precursors of the pyrimidine sugars and, with purines, of DNA and RNA. Note that in contrast to purines salvage takes place at the nucleoside not the base level in human cells and pyrimidine metabolism normally lacks any detectable end-product. The importance of this network is highlighted by the variety of clinical symptoms associated with the possible enzyme defects indicated. 23.10, Uridine monophosphate synthase (UMPS), 23.11a, uridine monophosphate hydrolase 1 (UMPHl), 23.12, thymidine phosphorylase (TP), 23.13, dihydropyrimidine dehydrogenase (DPD), 23.14, dihydropyrimidine amidohydrolase (DHP), 23.15, y -ureidopropionase (UP) (23.11b, UMPH superactivity specific to fibroblasts is not shown). CP, carbamoyl phosphate. The pathological metabolites used as specific markers in differential diagnosis are highlighted...

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

The common pyrimidine ribonucleotides are cytidine 5 -monophosphate (CMP cytidylate) and uridine 5 -monophosphate (UMP uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide biosynthesis (Fig. 22-36) proceeds in a somewhat different manner from purine nucleotide synthesis the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. Required in this process is carbamoyl phosphate, also an intermediate in the urea cycle (see Fig. 18-10). However, as we noted... 

Phaseolus vulgaris, Xanthiumpetmsylvanicum). LD50 (mouse p.o.) 2 g/kg, (mouse i. v.) 770 mg/kg. Biochemistry O. is a biosynthetic precursor of pyrimidine nucleotides. The biosynthesis proceeds from L- aspartic acid and carbamoyl phosphate with subsequent dehydrogenation. Reaction with 5-phospho-a-D-ribofuranose 1-diphosphate and loss of pyrophosphate furnishes OMP and, after decarboxylation, uridine 5 -monophosphate. This de novo synthesis of pyrimidine bases is an important biochemical process in the biosynthesis of nucleic acids (see LiO). For synthesis, see Lit.. ... 

The first step in de novo pyrimidine biosynthesis is the synthesis of carbamoyl phosphate from bicarbonate and ammonia in a multistep process, requiring the cleavage of two molecules of ATP. This reaction is catalyzed by carbamoyl phosphate synthetase (CPS), and the bicarbonate is phosphorylated by ATP to form carboxyphosphate and ADP (adenine dinucleotide phosphate). Ammonia then reacts with carboxyphosphate to form carbamic acid. The latter is phosphorylated by another molecule of ATP with the mediation of CPS to form carbamoyl phosphate, which reacts with aspartate by aspartate transcarbamoy-lase to form A-carbamoylaspartate. The latter cyclizes to form dihydroorotate, which is then oxidized by NAD-1- to generate orotate. Reaction of orotate with 5-phosphoribosyl-l-pyrophosphate (PRPP), catalyzed by pyrimidine PT, forms the pyrimidine nucleotide orotidylate. This reaction is driven by the hydrolysis of pyrophosphate. Decarboxylatin of orotidylate, catalyzed by orotidylate decarboxylase, forms uridylate (uridine-5 -monophosphate, UMP), a major pyrimidine nucleotide that is a precursor of RNA (Figure 6.53). 

With in vivo experiments, Hurlbert and Potter ) first showed that in rat liver, uridine nucleotides were intermediates in the conversion of orotate to nucleic acid pyrimidines the first of the three uridine phosphates to become labeled in this process was the monophosphate, uridylate (UMP) IS). The synthesis of uridylate from orotate takes place in two steps (a) the condensation of orotate with PP-ribose-P to form orotidylate (orotidine 5 -monophosphate, or OMP), and (b) decarboxylation of orotidylate. 

The final steps of pyrimidine biosynthesis novo which are catalyzed by two sequential enzymes, orotate phosphoribosyltransfer-ase (OPRT) and orotidylic decarboxylase (ODC), involve the PP-ribose P dependent conversion of orotic acid to orotidine-5 -monophosphate (OMP) followed by decarboxylation at the 7 position to form uridine 5 -monophosphate (UMP) (Fig. 1). UMP is then utilized further in the synthesis of nucleic acids and co-enzymes. Defects at this site in this metabolic pathway are important for they can result in "pyrimidine starvation" from depletion of the intracellular pool of pyrimidine nucleotides. In man the rare genetic disease, orotic aciduria, involves a deficiency of both OPRT and ODC (Type 1) (Smith, Sullivan and Huguley, 1961) or, less commonly, only ODC (Type II) (Fox, 0 Sullivan and Firken, 1969). 

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