Purine and pyrimidine nucleotide biosynthesis

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. 

Goordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs. 

PRPP affects purine and pyrimidine nucleotide biosynthesis. PRPP formation is activated by inorganic phosphate and inhibited by several end products of pathways that use PRPP. In the purine de novo pathway, PRPP activates amidophosphoribosyltransferase and is the rate-limiting substrate for the enzyme. In purine... 

In addition to the transphosphorylation reactions discussed in Chapter 4, there are several general types of carbon and nitrogen transfer reactions which also occur in purine and pyrimidine nucleotide biosynthesis and interconversion. Among these are one-carbon and phosphoribosyl transfer reactions, amino group transfer from glutamine and aspartate, and amide syntheses. In most of these processes carbon-nitrogen bonds... 

Cells are able to synthesize genetic material (DNA, RNA) from endogenous metabolites known as purine and pyrimidine nucleotides (Fig. 36-3). Certain anticancer drugs are structurally similar to these endogenous metabolites and compete with these compounds during DNA/RNA biosynthesis. These drugs are therefore called antimetabolites because they interfere with the normal metabolites during cellular biosynthesis.16,80... 

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). 

Phosphoribosyl-l-pyrophosphate (PRPP) is a key intermediate in nucleotide biosynthesis. It is required for de novo synthesis of purine and pyrimidine nucleotides and the salvage pathways, in which purines are converted to their respective nucleotides via transfer of ribose 1-phosphate group from PRPP to the base that is. 

Biosynthesis of purine and pyrimidine nucleotides requires carbon dioxide and the amide nitrogen of glutamine. Both use an amino acid... 

The synthesis of purine and pyrimidine nucleotides needed for the biosynthesis of nucleic acids, and in turn the processes of transcription and translation provide a number of suitable targets for therapeutic intervention. These have been subject of much interest for the discovery of new antiprotozoal drugs as well. Developments in two areas, viz. the purine salvage pathway and the pyrimidine biosynthesis have yielded useful drugs and are discussed. 

Biosynthesis and degradation of purines and pyrimidine nucleotides, gout, Lesch-Nyhan syndrome 290-292, 482, 483... 

Outline the regulation of the biosynthesis of the purine and pyrimidine nucleotides and name the committed steps in the pathways. 

Ribose phosphates phosphorylated derivatives of ribose. Ribose is phosphorylated in position 5 by the action of ribokinase (EC 2.7.1.15) and ATP ribose 5-phosphate is also produced in the Pentose phosphate cycle (see), and in the Calvin c cle (see) of photosynthesis. Phosphoribomutase cat yses the interconversion of ribose 5-phospbate and ribose 1-phosphate, and the cosubstrate of this reaction is ribose l,5-f>isphosphate. 5-Phosphoribosyl 1-pyrophos-phate donates a ribose 5-phosphate moiety in the de novo biosynthesis of purine and pyrimidine nucleotides (see Purine biosynthesis. Pyrimidine biosynthesis), in the Salvage pathway (see) of purine and pyrimidine utilization, in the biosynthesis of L-Histi-dine (see) and L-Tryptophan (see) and in the conversion of nicotinic acid into nicotinic acid ribotide (see Pyridine nucleotide cycle). Ribose 1-phosphate can also take part in nucleotide synthesis (see Salvage pathway). 

Purines are an integral part of ATP and of many coenzymes—such as NAD, FAD, and UDP— involved in important bioenergetic or biosynthetic reactions. The stepwise elucidation of the biosynthesis of purine and pyrimidine nucleotides from 1940 to 1960 might well be one of the most remarkable contributions to the development of modem biochemistry. 

The biosynthesis of both purine and pyrimidine nucleotides—and consequently the biosynthesis of ATP, coenzymes, and nucleic acids—depends upon the availability of PRPP. Therefore, it is important to establish whether in mammalian tissues the PRPP supplies outweigh the needs, or whether they are produced as needed. If the latter is true, PRPP biosynthesis will play a key role in regulating nucleotide biosynthesis. The question that we have just raised is not completely answered. No direct evidence indicates that PRPP is truly limiting, but indirect observations suggest that such limitations may exist. 

Synthetic analogs of purine and pyrimidine bases and their derivatives serve as anticancer dmgs either by inhibiting an enzyme of nucleotide biosynthesis or by being incorporated into DNA or RNA. 

Figure 34-7 summarizes the roles of the intermediates and enzymes of pyrimidine nucleotide biosynthesis. The catalyst for the initial reaction is cytosolic carbamoyl phosphate synthase II, a different enzyme from the mitochondrial carbamoyl phosphate synthase I of urea synthesis (Figure 29-9). Compartmentation thus provides two independent pools of carbamoyl phosphate. PRPP, an early participant in purine nucleotide synthesis (Figure 34-2), is a much later participant in pyrimidine biosynthesis.

The common pyrimidine ribonucleotides are cytidine 5 -monophosphate (CMP cytidylate) and uridine 5 -monophosphate (UMP uridylate), which contain the pyrimidines cytosine and uracil. De novo pyrimidine nucleotide biosynthesis (Fig. 22-36) proceeds in a somewhat different manner from purine nucleotide synthesis the six-membered pyrimidine ring is made first and then attached to ribose 5-phosphate. Required in this process is carbamoyl phosphate, also an intermediate in the urea cycle (see Fig. 18-10). However, as we noted... 

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. 

T There are several distinct types of inhibitors of nucleotide biosynthesis, each type acting at different points in the pathways to purine or pyrimidine nucleotides. All these inhibitors are very toxic to cells, especially rapidly growing cells, such as those of tumors or bacteria, because interruption of the supply of nucleotides seriously limits the cell s capacity to synthesize the nucleic acids necessary for protein synthesis and cell replication. In some cases, the toxic effect of such inhibitors makes them useful in cancer chemotherapy or in the treatment of bacterial infections. However, some of these agents can also damage the rapidly replicating cells of the intestinal tract and bone marrow. This danger imposes limits on the doses that can be used safely. 

Acivicin is a potent inhibitor of several steps in purine nucleotide biosynthesis that utilize glutamine. The enzymes it inhibits are glutamine PRPP amidotransferase (step 1, fig. 23.10), phosphoribosyl-A-formylglycinamidine synthase (step 4, fig. 23.10), and GMP synthase (see fig. 23.11). In pyrimidine nucleotide biosynthesis the enzymes inhibited are carbamoyl synthase (step 1, fig. 23.13) and CTP synthase (see fig. 23.14). Acivicin is under trial for the treatment of some forms of cancer. 

In eukaryotes, carbamoyl phosphate synthase is inhibited by pyrimidine nucleotides and stimulated by purine nucleotides it appears to be the most important site of feedback inhibition of pyrimidine nucleotide biosynthesis in mammalian tissues. It has been suggested that under some conditions, orotate phosphoribosyltransferase may be a regulatory site as well. 

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. 

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