Pyrimidine, and purine synthesis

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. 

Correct answer = C. Trimethoprim is 20 to 50 times more potent than sulfamethoxazole. It inhibits the enzyme dihydrofolate reductase, thus preventing both purine and pyrimidine synthesis. Trimethoprim resistance has been observed in gram-negative bacteria caused by the presence of a plasmid that codes for an altered dihydrofolate reductase with a lower affinity for the drug. 

Various aspects of bacterial nucleotides and nucleosides have been included in a number of recent reviews on such subjects as purine and pyrimidine synthesis, coenzymes, and carbohydrate polymers. ... 

Methotexate is an antineoplastic folic add analogue that blocks the conversion of dihydrofolate (FHj) to tetrahydro-folate (FH4) by binding to dihydrofolate reductase (DHFR) enzyme. Folate is essential for the normal synthesis of purines and pyrimidines, and therefore DNA and RNA. In order for folate to function as a cofactor, it must be reduced to FH by DHFR. Methotrexate binds to DHFR, prevents the conversion of FH2 to FH4, and, consequently, inhibits purine and pyrimidine synthesis. The antimetabolites are considered cell cycle specific, with most activity for cells in the S (synthesis) phase. With high-dose methotrexate, leucovorin rescue is often used to prevent severe toxicity to normal body tissues. Leucovorin (folinic acid) is a reduced form of folate (similar to FH ) that does not require the use of DHFR. Leucovorin is transported into healthy cells and is utilized for DNA and RNA synthesis. Tumor cells tend to have impaired transport mechanisms and usually cannot use leucovorin. Leucovorin is usually started within 24 to 36 hours of high-dose methotrexate administration and continues until methotrexate serum levels are below nontoxic levels (0.1 to 0.05 mol/L). 

Walsh, C. J., and Sherman, I. W. (1968b). Purine and pyrimidine synthesis by the avian malaria parasite, Plasmodium lophurae. J. Protozool. 15,763-770. 

Aspartate can be transaminated to form oxaloacetate, an intermediate of the citric-acid cycle. As with most transaminations, this is a reversible reaction, and aspartate can also be synthesized by a transamination reaction with glutamate and oxaloacetate to form aspartate and a-ketoglutarate. Therefore, aspartate is a nonessential amino acid. The aminotransferase with aspartate and a-ketoglutarate is particularly active in most tissues and occurs both in the mitochondria and the cytosol. The importance of this reaction is greater than simply forming the oxaloacetate or aspartate. Aspartate aminotransferase is an important reaction in the malate shuttle (see Chapter 11) wherein, reducing power can be transferred from the cytosol to the mitochondrion. Aspartate also plays a role in purine and pyrimidine synthesis and is particularly important in pyrimidine synthesis, where it donates both carbon and... 

Aspartate can be formed from oxaloacetate and glutamate, via transamination. This is important in urea synthesis, the malate shuttle, purine, and pyrimidine synthesis. 

A number of antimetabolites can be used to inhibit purine and pyrimidine synthesis and degradation. This is... 

Gutteridge, W. E. and Gaborak, M. (1979) A re-examination of purine and pyrimidine synthesis in the three main forms of Trypanosoma cruzi. Int. J. Biochem. 10 415-422. 

The reactions catalyzed by the epimerase, isomerase, transketolase, and transaldolase are all reversible reactions under physiologic conditions. Thus, ribose 5-phosphate required for purine and pyrimidine synthesis can be generated from intermediates of the glycolytic pathway, as well as from the oxidative phase of the pentose phosphate pathway. The sequence of reactions that generate ribose 5-phos-phate from intermediates of glycolysis is indicated below. 

One-carbon methyl donors for tetrahydrofolate and SAM Glycine, serine, histidine, methionine Most cells, but highest in liver Choline, phosphatidylcholine, purine and pyrimidine synthesis, inactivation of waste metabolites and xenobiotics through methylation. 

Feedback repression is the inhibition of formation of one or more enzymes in a pathway by a derivative of the end product. In many (but not all) amino acid biosynthetic pathways, the amino add end product must first combine with its transfer RNA (tRNA) before it can cause repression. Feedback repression is a widespread regulatory device especially for the synthesis of molecules intended for incorporation into macromolecules, e.g. amino adds, purines, and pyrimidines. Synthesis of vitamins also appears to be controlled by feedback repression, as well as by catabolite regulation (Birnbaum et al, 1967 Sasaki, 1965 Newell and Tucker, 1966 Wilson and Pardee, 1962 Papiska and Lichstein, 1968). Regulation of vitamin synthesis is important since only a small number (probably about 1000) of vitamin molecules are required per cell whereas many molecules of an average amino acid (probably 50 million) are required. An extremely wasteful case of vitamin overproduction would develop if enzymes for vitamin synthesis were produced at the same rate and were as active as the amino acid biosynthetic enzymes. 

Figure 6.2. Scheme of the mechanism of action of anti-folic antimalarials. PABA represents p-aminobenzoic acid, A andB the intracellular forms of dihydrofolic and tetrahydro-folic acids, and CoF is the enzyme co-factor for purine and pyrimidine synthesis... 

Salvage pathway utilization of preformed purine and pyrimidine bases for nucleotide synthesis In addition to de novo synthesis, the S.p. represents an alternative pathway for formation of purine and pyrimidine nucleotides In mutant microorganisms lacking de novo purine and pyrimidine synthesis, the S.p. is the only route for nucleotide syntheris following administration of exogenous purine and pyrimidine bases... 

Folate (folic acid and folacin) is a water-soluble B vitamin that is necessary in forming coenzymes for purine and pyrimidine synthesis, erythropoiesis, and methionine regeneration. 

Cat brain required uridine and cytidine from the liver and apparently did not utilize de novo synthetic reactions 457). Several tumors have been studied and were found to possess the de novo pathway for purine and pyrimidine synthesis 310, 455). 

Folate in its active form, THF, is a carrier of 1-carbon fragments, is used to convert homocysteine to methionine or is used in purine and pyrimidine synthesis, for example the formation of thymidylate. 

The N-5 position is considerably more basic than the N-10 position, and this basicity is one of several factors that control certain preferences in the course of reactions involving tetrahydrofolate. Thus, for-mylation occurs more readily at N-10 while alkylation occurs more readily at N-5. Benkovic and Bullard (1973) have reviewed evidence for an iminium cation at N-5 as the active donor in formaldehyde oxidation-level transfers. Recently, Barrows et al. (1976) have further studied such a mechanism for folic acid. The interconversion of these forms of folate coenzymes by enzymatic means has been reviewed by Stokstad and Koch (1967), and the reader is directed there for further details. Folate coenzymes are involved in a wide variety of biochemical reactions. These include purine and pyrimidine synthesis, conversion of glycine to serine, and utilization and generation of formate. In addition, the catabolism of histidine, with the formation of formiminoglu-tamic acid (FIGLU), is an important cellular reaction involving folate. 

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