Pyrimidine ribonucleotide synthesis precursors

IMP Is Converted into AMP and GMP Synthesis of Pyrimidine Ribonucleotides de Novo UMP Is a Precursor of Other Pyrimidine Nucleotides... 

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. 

Pemetrexed is chemically similar to folic acid. It inhibits three enzymes used in purine and pyrimidine synthesis - thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA. In 2004 it was approved for treatment of malignant pleural mesothelioma and as a second-line agent for the treatment of non-small cell lung cancer. Adverse effects include gastrointestinal complaints, bone marrow suppression, alopecia, allergic and neurotoxic reactions. 

Both the pyrimidines and the purines are built up from small precursor molecules which are readily available in the metabolic pool (page 185). The free bases are not synthesized as such but, while being assembled, the partially constructed ring structure reacts with a special phosphorylated pentose known as PRPP (5-phosphoribosyl-l-pyrophosphate) and forms a ribonucleotide. The deoxyribonucleotides, with the exception of TMP which is formed by methylation of deoxyuridylate, are formed by reduction of the corresponding ribonucleoside diphosphate. The conversion is precisely controlled by allosteric effects which ensure that all four deoxyribonucleotides are available in amounts appropriate for nucleic acid synthesis. 

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