Purine bases biosynthesis

The present researches were carried out in order to ascertain the effect of glucocorticoid hormones on all purine based biosynthesis in different rat organs ... 

The amino acid histidine has important functions in the active centres of several enzymes. Its biosynthesis involves intermediates which are possibly related to a precursor molecule (purine base) of a ribozyme. 

The nucleotides are among the most complex metabolites. Nucleotide biosynthesis is elaborate and requires a high energy input (see p. 188). Understandably, therefore, bases and nucleotides are not completely degraded, but instead mostly recycled. This is particularly true of the purine bases adenine and guanine. In the animal organism, some 90% of these bases are converted back into nucleoside monophosphates by linkage with phosphori-bosyl diphosphate (PRPP) (enzymes [1] and [2]). The proportion of pyrimidine bases that are recycled is much smaller. 

Aspartic acid and arginines are important substrates for the biosynthesis of purine bases. They are also glycosylation sites in proteins. These reasons have been at the origin of the synthesis of their mono and difluoro analogues. 

The next nine steps in purine nucleotide biosynthesis leading to the synthesis of IMP (whose base is hypoxanthine) are illustrated in Figure 22.7. This pathway requires four ATP molecules as an energy source. Two steps in the pathway require N10-formyltetrahydrofolate. 

The biosynthetic pathway to pyrimidine nucleotides is simpler than that for purine nucleotides, reflecting the simpler structure of the base. In contrast to the biosynthetic pathway for purine nucleotides, in the pyrimidine pathway the pyrimidine ring is constructed before ribose-5-phosphate is incorporated into the nucleotide. The first pyrimidine mononucleotide to be synthesized is orotidine-5 -monophosphate (OMP), and from this compound, pathways lead to nucleotides of uracil, cytosine, and thymine. OMP thus occupies a central role in pyrimidine nucleotide biosynthesis, somewhat analogous to the position of IMP in purine nucleotide biosynthesis. Like IMP, OMP is found only in low concentrations in cells and is not a constituent of RNA. 

Tetrahydrofolic acid (THF) is a coenzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and are required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing it-more precisely DHF-ffom precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

The pathways for the biosynthesis of nucleotides fall into two classes de novo pathways and salvage pathways (Figure 25.1). In de novo (from scratch) pathways, the nucleotide bases are assembled from simpler compounds. The framework for a pyrimidine base is assembled first and then attached to ribose. In contrast, the framework for a purine base is synthesized piece by piece directly onto a ribose-based structure. These pathways comprise a small number of elementary reactions that are repeated with variation to generate different nucleotides, as might be expected for pathways that appeared very early in evolution. In salvage pathways, preformed bases are recovered and reconnected to a ribose unit. 

HGPRT was considered a minor player in the "salvage" pathway that permitted reutilization of purine bases. The severity of Lesch-Nyhan syndrome suggests a more important role. Most likely the enz)one has an essential role in non-hepatic tissues where biosynthesis of purines occurs at a very low rate. Non-hepatic tissues contain the enzyme but depend on circulating purines and nucleosides to form nucleotides. 

Two of the more important purine analogs in use clinically are 6-mercaptopurine and 6-thioguanine. These purine antagonists and glutamine antagonists such as azaserine (Table 4-6) are major antagonists in the biosynthesis of purine bases. Before understanding the mechanism of their action, it is necessary to look at the biosynthesis of inosinic acid, the purine ribonucleotide that is the precursor to both purine bases found in DNA and RNA... 

Hypoxanthine is a base found in an intermediate of purine nucleotide biosynthesis. Figure 22.4 summarizes the pathway leading from phosphoribosyl-1-pyrophosphate (PRPP) to the first fully formed purine nucleotide, inosine 5 -monophosphate (IMP), also called inosinic acid. IMP contains as its base, hypoxanthine. 

In mammals, purine ribonucleotides are synthesized de novo from amino acids, ribose, carbon dioxide and formate as well as from preformed purine bases and nucleosides through salvage pathways. The general route for de novo biosynthesis is the same in those species of mammals, birds, yeasts and bacteria that have been studied (1). Parasitic protozoans and helminths cannot synthesize purines de novo and thus rely solely on salvage pathways (2-12). 

Fig. 41.4. The first step in purine biosynthesis. The purine base is built on the ribose moiety. The availability of the substrate PRPP is a major determinant of the rate of this reaction.

AP (apuiinic) site a site, lacking a purine base in DNA, that IS targeted by repair enzymes (10.5) arachidonic acid a fatty acid that contains 20 carbon atoms and 4 double bonds the precursor of prostaglandins and leukotrienes (8.8) aspartate transcarbamo)lase (ATCase) a classic example of an allosteric enzyme that catalyzes an early reaction in pyrimidine biosynthesis (6.5)... 

IMP is the product of the pathway for de novo purine biosynthesis and the precursor of AMP and GMP. With the de novo pathway for purines not working effectively, it would be helpful to stimulate the salvage pathway, perhaps with a diet that is rich in nucleotides that would then be a source of the preformed purine bases hypoxanthine, adenine, and guanine. 

As described in the previous section, in the biosynthesis of inosinic acid, ribose combines with the purine base in the initial stages of purine skeleton synthesis. On the other hand, in the biosynthesis of the pyrimidine nucleosides, ribose is introduced after the completion of the synthesis of the... 

It seems certain that the effect of SAB on the cytotoxicity and DNA repair of cells treated with monofunctional alkylating agents is mediated via an inhibition of ADP-ribosyl transferase activity (7, 8). Nevertheless, the pleiotropic effects of SAB could result in the modulation of the cytotoxicity of other dmgs independent of ADP-ribosyl transferase inhibition. In this paper, we describe the cytotoxic effects of SAB on a range of purine base and nucleoside analogues. The data lead us to hypothesize that SAB modulates purine analogue cytotoxicity by mechanism(s) independent of DNA repair inhibition, but involving effects on de novo purine biosynthesis and nucleoside transport. 

A number of purine nucleotide analogues can mimic the effects of natural purine ribonucleotides on PP-ribose-P amidotransferase and thereby effect feedback inhibition of the entire pathway (69, 60). Such nucleotide analogues may be synthesized by cells from purine bases or nucleosides presented to them. A number of compounds with potent inhibitory properties, such as 6-mercaptopurine, 6-thioguanine, and 6-methylmercaptopurine ribonucleoside, inhibit purine biosynthesis de novo in this way, although it is not known whether this action is responsible for the growth inhibition. 

Purine bases are a group of compounds found in plants and animals —they include nucleic acids. Their biosynthesis is complex with numerous non-amino-acid precursors (Samuelsson 1992). Xanthine, an oxidised purine that occurs as a breakdown product of nucleic acid metabolism, is itself oxidised in the body to uric acid. Xanthine consists of two fused ring systems each containing two nitrogen atoms. 

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