Purine and pyrimidine biosynthesis

The bases occurring in nucleic acids are derivatives of the aromatic heterocyclic compounds purine and pyrimidine (see p. 80). The biosynthesis of these molecules is complex, but is vital for almost all cells. The synthesis of the nucleobases is illustrated here schematically. Complete reaction schemes are given on pp. 417 and 418. 

The pyrimidine ring is made up of three components the nitrogen atom N-1 and carbons C-4 to C-6 are derived from aspartate, carbon C-2 comes from HCOa , and the second nitrogen (N-3) is taken from the amide group of glutamine. 

The synthesis of the purine ring is more complex. The only major component is glycine, which donates C-4 and C-5, as well as N-7. All of the other atoms in the ring are incorporated individually. C-6 comes from HCOa . Amide groups from glutamine provide the atoms N-3 and N-9. The amino group donor for the inclusion of N-1 is aspartate, which is converted into fumarate in the process, in the same way as in the urea cycle (see p. 182). Finally, the carbon atoms C-2 and C-8 are derived from formyl groups in N °-formyl-tetrahydrofolate (see p. 108). 

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. 

The precursors for the synthesis of the pyrimidine ring are carbamoyl phosphate, 

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Purine and pyrimidine biosynthesis parallel one another mole for mole, suggesting coordinated control of their biosynthesis. Several sites of cross-regulation characterize purine and pyrimidine nucleotide biosynthesis. The PRPP synthase reaction (reaction 1, Figure 34-2), which forms a precursor essential for both processes, is feedback-inhibited by both purine and pyrimidine nucleotides. 

Function To donate methyl groups to phospholipid, biogenic amines, thymidine, and amino acid biosynthesis To provide one-carbon fragments at the level of formaldehyde and formic acid for purine and pyrimidine biosynthesis Location Most everywhere... 

Folic acid derivatives are essential for DNA synthesis, in that they are cofactors for certain reactions in purine and pyrimidine biosynthesis, including the uracil-thymine methylation just described. They are also cofactors for several reactions relating to amino acid metabolism. The folic acid system thus offers considerable scope for drug action. 

The de novo pathways for purine and pyrimidine biosynthesis appear to be nearly identical in all living organisms. Notably, the free bases guanine, adenine, thymine, cytidine, and uracil are not intermediates in these pathways that is, the bases are not synthesized and then attached to ribose, as might be expected. The purine ring structure is built up one or a few atoms at... 

A5-Methyltetrahydrofolate is the methyl-group donor substrate for methionine synthase, which catalyzes the transfer of the five-methyl group to the sulfhydryl group of homocysteine. This and selected reactions of the other folate derivatives are outlined in figure 10.15, which emphasizes the important role tetrahydrofolate plays in nucleic acid biosynthesis by serving as the immediate source of one-carbon units in purine and pyrimidine biosynthesis. 

A large number of compounds in category 3 act at different sites in the pathways for purine and pyrimidine biosynthesis. These compounds are very toxic for rapidly growing tumors and bacteria, making them useful in cancer chemotherapy and treatment of bacterial infections. 6-Mercaptopurine is a potent inhibitor of purine biosynthesis, and 5-fluorouracil inhibits thymidylate synthesis. Some compounds, such as hydroxyurea and sulfonamides, inhibit the synthesis of both purine and pyrimidine nucleotides. These are only a few of the many compounds useful in treating cancer and infectious diseases (see Chapter 10). 

The action on bacteria of sulfonamides and structural analogs of purines and pyrimidines has been the subject of many publications. In the course of these studies, a number of nucleosides and nucleotides have been isolated which, in certain cases, have provided valuable information about purine and pyrimidine biosynthesis. 

De novo purine and pyrimidine biosynthesis occurs in the liver and, to a limited extent, in the brain. 

Storage form of ammonia in tissue supplies the amido nitrogen used in purine and pyrimidine biosynthesis... 

Synthesis of the amino acids Eleven of the twenty common amino acids can be synthesized in the body (Fig. 39.1). The other nine are considered essential and must be obtained from the diet. Almost all of the amino acids that can be synthesized by humans are amino acids used for the synthesis of additional nitrogen-containing compounds. Examples include glycine, which is used for porphyrin and purine synthesis glutamate, which is required for neurotransmitter and purine synthesis and aspartate, which is required for both purine and pyrimidine biosynthesis. 

Table 5-III lists the glutamine amide transfer reactions of purine and pyrimidine biosynthesis de novo, and of purine and pyrimidine ribonucleotide interconversion, and several more that occur in other areas of metabolism. All have features in common 1, 3).

In spite of the large number of folate derivatives, all the folate coenzymes have a similar function in metabolism. The folate coenzyme activates 1-carbon units (methyl, methylene, and formyl) and facilitates their transfer from one metabolite to another. A 1-carbon unit is transferred principally in amino acid conversion and in purine and pyrimidine biosynthesis. Many of the reactions involving folate coenzymes are discussed in other chapters, so these reactions are reviewed only briefly here. 

N. Z5liner and W. Grdbner. Dietary feedback regulation of purine and pyrimidine biosynthesis in man. 

Dietary feedback regulation of purine and pyrimidine biosynthesis in man. 

PURINE AND PYRIMIDINE BIOSYNTHESIS IN NEUROSPORA CRASSA AND HUMAN SKIN PIBROBIASTS.ALTERATION BY RIBOSIDES AND RIBOTIDES OP ALIOPURINOL AND OXIPURINOL... 

Allopurinol and oxipurinol inhibit according to Kelley et al. (1,2) both de novo purine and pyrimidine biosynthesis in human fibroblast cultures. This effect (at least at higher concentrations) was shown not to be dependent on the presence of xanthine oxidase or HGPRTase, so that it has to be attributed to some other mechanism than inhibition by allopurinol-ribo-nucleotide. 

We studied the effects of allopurinol, allopurinol-1-ribonucleoside, allopurinol-1-ribonucleotide and oxipurinol, oxipurinol-7-rlbonucleoside, oxipurinol-7-ribonucleotide on purine and pyrimidine biosynthesis in cultures of Neurospora crassa (wild strain 74 a) and human fibroblasts. 

I. Influence of allopurinol- or oxipurinolribo-nucleosides and -ribonucleotides on purine and pyrimidine biosynthesis in Neurospora crassa. 

The inhibitory effects of allopurinol and oxipurinol on purine and pyrimidine biosynthesis in human fibroblasts could be explained by formation of their respective ribonucleotides either by HGPRTase (allopurinol) or OPRTase (oxipurinol). The effects of allopurinol-1-ribonucleoside are hardly to be explained. Theoretically the allopurinol-1-ribonucleoside can be converted either to the free base (catalyzed by a purine nucleoside phosphorylase) or to allopurinol-1-ribonucleotide (catalyzed by a nucleoside kinase). According to Utter et al. (4) there seems however to be a lack of kinases in mammals which effectively phosphorylate inosine. Furthermore, indirect experiments of Elion et al. (5), where no detectable nucleotide formation or incorporation into nucleic acids was observed in vivo with Hc-allopurinol would support this. Nevertheless, our results would claim for a direot conversion of allopurin-ol-1-ribonucleoside to allopurinol-1-ribonucleotide in human fibroblast, at least at doses from 10 5 -to 10-3 M. Otherwise we would have to explain the inhibitory effects of allopurinol-1-ribonucleoside by direct influences on purine synthesis, for the other possibility theoretical-... 

Our results could not conclusively explain the mechanisms for allopurinol- and oxipurinol-mediated inhibition of purine and pyrimidine biosynthesis. Most of our results are in accordance with the view that allopurinol-1-ribonucleotide and oxipurinol-7-ribonucleo-tide are to be accounted for the inhibitory effects on both purine and pyrimidine biosynthesis. Relatively high concentrations of allopurinol-1-ribonucleoside and oxipurinol-7-ribonucleoside have Inhibitory effects which are difficult to explain with the view that there exist no inosinic or uridine specific kinases in fibroblasts, catalyzing to the respective ribonucleotides. 

We hope that time kinetic studies, the studies with cell homogenates and combination of inhibitory substances to see potentiating effects will give additional clue to the molecular action of these substances on purine and pyrimidine biosynthesis. 

VIII. Feedback Control of Purine and Pyrimidine Biosynthesis. 443... 

A number of chemical compoimds which inhibit purine and pyrimidine biosynthesis are not obviously related in structure to any of the intermediates of the de novo synthetic pathway. Urethane can inhibit the growth of certain tumours, cause the formation of abnormal mitoses, and damage chromosomes. It is also... 

Purine and Pyrimidine Biosynthesis in Neurospora Crassa and Human Skin Fibroblasts. Alteration by Ribosides and Ribotides of... 

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