Pyrimidines/pyrimidine nucleotides

Pyrimidines Pyrimidine nucleotides (1) Pyrimidines (ii) Nucleotides derived from pyrimidines Meat... 

Proteias are metabolized coatiauously by all living organisms, and are ia dyaamic equilibrium ia living cells (6,12). The role of amino acids ia proteia biosyathesis has beea described (2). Most of the amino acids absorbed through the digestioa of proteias are used to replace body proteias. The remaining portioa is metabolized iato various bioactive substances such as hormones and purine and pyrimidine nucleotides, (the precursors of DNA and RNA) or is consumed as an energy source (6,13). 

In another series of experiments, a novel approach to the determination of nucleotide sequence was adopted by A. S. Jones, Stacey, and their co-workers. For example, when calf thymus DNA was treated with mercaptoacetic acid in the presence of zinc chloride and anhydrous sodium sulfate, it yielded aldehydo-apurinic acid bis(carboxymethyl) dithioacetal. When degraded with dilute alkali, this afforded dialyzable fragments, which were separated into at least 20 components. Some were identified, including mono-, di-, and tri-nucleotides, thereby revealing that DNA contain regions of at least three linked pyrimidine nucleotides. The same procedure was applied to the DNA isolated from M. phlei ... 

Finally, the pyrimidine nucleotide 4-thiouridine 5 -triphosphate, also presumably essentially in the syn conformation, cannot serve as a substrate for homopolymerization with E. coli RNA polymerase (54). Small amounts of 4-thiouridine were reported to have been found in naturally occurring transfer RNA from coli (55). Scheit has reported that as a monomer in CDCI3, the base can still pair with adenosine (56). 

Figure 20-7. Summary of the interrelationships in metabolism of amino sugars. (At asterisk Analogous to UDPGIc.) Other purine or pyrimidine nucleotides may be similarly linked to sugars or amino sugars. Examples are thymidine diphosphate (TDP)-glucosamine and TDP-N-acetylglucosamine.

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.

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

Reaction 12 of Figure 34—7 is the only reaction of pyrimidine nucleotide biosynthesis that requires a tetrahydrofo-late derivative. The methylene group of A A Tmethyl-ene-tetrahydrofolate is reduced to the methyl group that is transferred, and tetrahydrofolate is oxidized to dihydro-... 

Certain Pyrimidine Analogs Are Substrates for Enzymes of Pyrimidine Nucleotide Biosynthesis... 

The activities of the first and second enzymes of pyrimidine nucleotide biosynthesis are controlled by allosteric... 

Purine Pyrimidine Nucleotide Biosynthesis Are Coordinately Regulated... 

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. 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Excess carbamoyl phosphate exits to the cytosol, where it stimulates pyrimidine nucleotide biosynthesis. The resulting mild orotic aciduria is increased by high-nitrogen foods. 

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

Information within the single strand of RNA is contained in its sequence ( primary strucmre ) of purine and pyrimidine nucleotides within the polymer. The sequence is complementary to the template strand of the gene from which it was transcribed. Because of this... 

Twenty different amino acids are required for the synthesis of the cellular complement of proteins thus, there must be at least 20 distinct codons that make up the genetic code. Since there are only four different nucleotides in mRNA, each codon must consist of more than a single purine or pyrimidine nucleotide. Codons consisting of two nucleotides each could provide for only 16 (4 ) specific codons, whereas codons of three nucleotides could provide 64 4 ) specific codons. 

The anticodon region consists of seven nucleotides, and it recognizes the three-letter codon in mRNA (Figure 38-2). The sequence read from the 3 to 5 direction in that anticodon loop consists of a variable base-modified purine-XYZ-pyrimidine-pyrimidine-5h Note that this direction of reading the anticodon is 3 " to 5 whereas the genetic code in Table 38—1 is read 5 to 3 since the codon and the anticodon loop of the mRNA and tRNA molecules, respectively, are antipar-allel in their complementarity just like all other inter-molecular interactions between nucleic acid strands. 

Substantial attention has been devoted to the metabolism of 5-fluorouracil and related compounds. For example, F NMR was used successfully both in cell extracts and in whole mycelia to elucidate anabolic reactions involving pyrimidine nucleotides and degradation to a-fluoro-p-alanine in the fungus Nectria haematococca (Parisot et al. 1989,1991). 

Under low oxygen conditions, C5 -sugar radicals can react with the base residue on the same nucleotide. In purine nucleotides, the carbon-centered radical 91 can add to the C8-position of the nucleobase (Scheme 8.31). Oxidation of the intermediate nucleobase radical 92 yields the 8,5 -cyclo-2 -deoxypurine lesion 93197,224,225,230-233 Similarly, in pyrimidine nucleotides, the C5 -radical can add to the C6-position of nucleobase. Reduction of the resulting radical intermediate yields the 5, 6-cyclo-5,6-dihydro-2 -deoxypyrimidine lesion 94,234-236... 

Ozonolysis of organic compounds in water also has biological and environmental93 interest. Ozone preferentially attacks the base moiety of pyrimidine nucleotides in water.94 For example, the reaction of ozone with uracil in water, having no substitutent at 1-position, gave the ozonolysis products in Scheme 3.6.95 The reactions of DNA and RNA with O3 in an aqueous environment are linked to the damage of... 

Pyrimidine 5 -nucleotidase (P5N) is a unique enzyme that was recognized from studies of families with relatively common hemolytic disorders. The enzyme catalyzes the hydrolytic dephosphorylation of pyrimidine 5 -nucleotides but not purine nucleotides. The role of this enzyme is to eliminate RNA and DNA degradation products from the cytosol during erythroid maturation by conversion of nucleotide monophosphates to diffusible nucleosides. P5N is inhibited by lead, and its activity is considered to be a good indicator of lead exposure (PI). 

Fig. 12. Absorption spectra of perchloric acid extracts of whole blood from normal subject and a patient with pyrimidine 5 -nucleotides (P5N) deficiency. Absorption peak shift occurs in P5N deficiency, reflecting intracellular accumulation of pyrimidine nucleotides.

The increase in erythrocyte destruction may be due in part to inhibition by lead of pyrimidine-5 -nucleotidase, which results in an accumulation of pyrimidine nucleotides (cytidine and uridine phosphates) in the erythrocyte or reticulocyte. This enzyme inhibition and nucleotide accumulation affect erythrocyte membrane stability and survival by alteration of cellular energetic (Angle et al. 1982 EPA 1986a). Formation of the heme-containing cytochromes is inhibited in animals treated intraperitoneally or orally... 

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