Purine ribonucleotide synthesis pathways

The two classes of nucleotide that must be synthesised are the pyrimidine and purine ribonucleotides for RNA synthesis and the deoxyribonucleotides for DNA synthesis. For the original sources of the nitrogen atoms in the bases of the pyrimidine and purine nucleotides, see Figure 20.7. The pathway for the synthesis of the pyrimidine nucleotides is... 

Purine deoxyribonucleotides are derived primarily from the respective ribonucleotide (Fig. 6.2). Intracellular concentrations of deoxyribonucleotides are very low compared to ribonucleotides usually about 1% that of ribonucleotides. Synthesis of deoxyribonucleotides is by enzymatic reduction of ribonucleotide-diphosphates by ribonucleotide reductase. One enzyme catalyzes the conversion of both purine and pyrimidine ribonucleotides and is subject to a complex control mechanism in which an excess of one deoxyribonucleotide compound inhibits the reduction of other ribonucleotides. Whereas the levels of the other enzymes involved with purine and pyrimidine metabolism remain relatively constant through the cell cycle, ribonucleotide reductase level changes with the cell cycle. The concentration of ribonucleotide reductase is very low in the cell except during S-phase when DNA is synthesized. While enzymatic pathways, such as kinases, exist for the salvage of pre-existing deoxyribosyl compounds, nearly all cells depend on the reduction of ribonucleotides for their deoxyribonucleotide... 

Fig. 3. The pathway of de novo purine ribonucleotide biosynthesis. The pathway includes the synthesis of PRPP, which is also used in the synthesis of pyrimidines, pyridine nucleotides, histidine, and tryptophan in plants. The enzymes catalyzing the numbered reactions are (1) PRPP synthetase, (2) PRPP amidotransferase, (3) GAR synthetase, (4) GAR transformylase, (5) FGAR amidotransferase, (6) AIR synthetase, (7) AIR carboxylase, (8) succino-AICAR synthetase, (9) adenylosuccinase, (10) AICAR transformylase, and (11) IMP cyclohydrolase.

As discussed in the previous section, the synthesis of ribose 5-phosphate must be quite high to provide the ribose 5-phosphate required for de novo purine ribonucleotide biosynthesis. Ribose 5-phosphate required for PRPP synthesis can be synthesized de novo via the oxidative or nonoxidative arms of the pentose phosphate pathway or by recycling of ribose released by the action of nucleotidases/nucleosidases (Fig. 5). The latter pathway requires ribose phosphotransferase (ribokinase), which has been detected in soybean and pea nodule extracts (Christensen and Jochimsen, 1983). The efficient recycling of ribose could eliminate the need for the continuous production of ribose 5-phosphate. Two enzymes of the oxidative branch of the pentose phosphate... 

PRPP is the activated intermediate in the synthesis of phosphoribosylamine in the de novo pathway of purine formation of purine nucleotides from free bases by the salvage pathway of orotidylate in the formation of pyrimidines of nicotinate ribonucleotide of phosphoribosyl ATP in the pathway leading to histidine and of phosphoribosylanthranilate in the pathway leading to tryptophan. 

Purine nucleotides can be produced by two different pathways. The salvage pathway utilizes free purine bases and converts them to their respective ribonucleotides by appropriate phosphoribosyltransferases. The de novo pathway utilizes glutamine, glycine, aspartate, N -formyl FH4, bicarbonate, and PRPP in the synthesis of inosinic acid (IMP), which is then converted to AMP and GMP. 

Pemetrexed is a multitargeted antifolate that inhibits at least three biosynthetic pathways in thymidine and purine synthesis (see Table 124—11). In addition to inhibition of DHFR, it also inhibits thymidine synthase and glycinamide ribonucleotide formyltransferase, decreasing the risk of development of drug resistance. Supplementation of folic acid and vitamin B12 is required to decrease myelosuppression... 

The de novo pathway of purine synthesis is complex, consisting of 11 steps, and requiring 6 molecules of ATP for every purine synthesized. The precursors that donate components to produce purine nucleotides include glycine, ribose 5-phosphate, glutamine, aspartate, carbon dioxide, and N -formyl FH4 (Fig. 41.1). Purines are synthesized as ribonucleotides, with the initial purine synthesized being inosine monophosphate (IMP). Adenosine monophosphate (AMP) and guano sine monophosphate (GMP) are each derived from IMP in two-step reaction pathways. 

Two reactions that are required to form the precursors of DNA are described in detail ribonucleotide reductase converts ribonucleotides to deoxyribonucleotides, and thymidylate synthase methylates dUMP to form dTMP. The authors present the mechanisms and cofactors of these enzymes and explain how some anticancer drugs and antibiotics function by inhibition of dTMP synthesis and thus the growth of cells. Nucleotides also serve important roles as constituents of NAD", NADP, FAD, and coenzyme A (CoA), so the syntheses of these cofactors are described briefly. The chapter concludes with an explanation of how the purines are catabolized and some of the pathological conditions that arise from defects in the catabolic pathway of the purines. 

Biosynthesis and function of RNA - Mcmy inhibitors of RNA synthesis, such as aotinomycin, act by complexing with DNA and inhibiting its template function in the biosynthesis of RNA.3 Base analogs, such as 6-mercapto-purine and 8-azaguanine, interfere with interconversions of ribonucleotide subunits and inhibit novo synthesis of RNA.3 Utilization of these biochemical pathways for the design of chemotherapeutic agents is limited by considerations similar to those discussed for inhibitors of DNA synthesis. 

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...

The purine salvage pathway enzyme HGPRT phosphoribosylates hypoxanthine and guanine, which allows the free bases to be reused as precursors for nucleic acid synthesis. The purine analogues, 8-azaguanine (8AG) and 6-thioguanine (6TG), are also substrates for HGPRT. After further phosphorylation, 8AG and 6TG ribonucleotides become substrates for nucleic... 

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