Pyrimidine ribonucleotide synthesis pathway

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... 

In animal cells engaged in DNA synthesis, deoxyuridine can be incorporated without cleavage into DNA thymidylate, but phosphorolysis also occurs and the uracil so released will not have incorporation into DNA as a specific metabolic fate. Because of deamination, deoxycytidine may be converted to either of the pyrimidine nucleotides of DNA cleavage of the deamination product, deoxyuridine, liberates uracil which may enter the pathways of pyrimidine ribonucleotide metabolism. 

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 atoms of the pyrimidine ring are derived from two amino acids, aspartate and glutamine, and carbon dioxide (Figure 16.6a). Biosynthesis does not produce free heterocyclic compounds but nucleotides. The synthetic pathway produces uridine ribonucleotides which also serve as the precursors of other pyrimidine ribonucleotides and deoxyribo-nucleotides. The cellular pool of free deoxyribo-nucleotides is normally held at an extremely low level but requires enhancement to support the synthesis of DNA when cells prepare for division. 

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... 

The biosynthetic pathway to UMP starts from carbamoyl phosphate and results in the synthesis of the pyrimidine orotate, to which ribose phosphate is subsequently attached. CTP is subsequently formed from UTP. Deoxyribonucleotides are formed by reduction of ribonucleotides (diphosphates in most cells). Thy-midylate is formed from dUMP. 

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. 

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.

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