Pyrimidine nucleotides derivatives

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-... 

Another important vitamin is folate, which is required for purine and pyrimidine nucleotide synthesis. Since folate and its derivatives are generally lipo-phobic anions, they do not traverse biological membranes via simple diffusion but rather have to be taken up into the cells by specific transport processes... 

Fluorouracil and fluorodeoxyuridine (floxuridine) inhibit pyrimidine nucleotide biosynthesis and interfere with the synthesis and actions of nucleic acids. To exert its effect, fluorouracil (5-FU) must first be converted to nucleotide derivatives such as 5-fluorodeoxyuridylate (5-FdUMP). Similarly, floxuridine (FUdR) is also converted to FdUMP by the following reactions ... 

Enzymes which catalyze the hydrolysis of the unit linkage of sequential residues of oligomers or polymers determine their substrate specificity by recognizing the particular unit residue in the sequential chain as well as the direction of the chain. For example, ribonuclease cleaves the 3 -phosphate of a pyrimidine nucleotide residue but not the 5 -phosphate, and trypsin hydrolyzes peptide bonds which involve the arginine or lysine residue at the carbonyl end but not at the amino end. This is also the case for the hydrolysis of a variety of synthetic substrates and quasi-substrates (Sect. 4.1). Synthetic trypsin substrates are ester or amide derivatives in which the site-specific group (positive charge) is contained in their carbonyl portion. 

The atoms of the pyrimidine ring are derived from carbamoyl phosphate and aspartate, as shown in Fig. 15-14. The de novo biosynthesis of pyrimidine nucleotides is shown in Fig. 15-15. The first completely formed pyrimidine ring is that of dihydroorotate. Only after oxidation to orotate is the ribose attached to produce orotidylate. The compound 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP) provides the ribose phosphate. L-Glutamine is used as a substrate donating nitrogen atoms at reactions 1 and 9, catalyzed by carbamoyl phosphate synthetase II and CTP synthetase, respectively a second... 

The nomenclature of nucleotides and their constituent units was presented earlier (Section 5.1.2). Recall that a nucleoside consists of a purine or pyrimidine base linked to a sugar and that a nucleotide is a phosphate ester of a nucleoside. The names of the major bases of RNA and DNA, and of their nucleoside and nucleotide derivatives, are... 

The utilization of ammonia resulting from the combination of carbamyl phosphate with aspartic acid, the initial reaction for the synthesis of the pyrimidine nucleotides, continues only as long as there is a requirement for them (Fig. 3). Regulation of this biosynthetic pathway is probably by way of feedback inhibition of aspartate transcarbamylase. The rat liver enzyme is inhibited by uridine, cytidine or thymidine or such derivatives as CMP, UTP, or TMP, all intermediates or products of this pathway (B8). This is not the only enzyme of the pathway which may be subject to feedback regulation. Dihydroorotase from rat liver is also inhibited by some pyrimidines and purines (B9). 

This amide of glutamic acid has properties similar to those of asparagine. The y-amido nitrogen, derived from ammonia, can be used in the synthesis of purine and pyrimidine nucleotides (Chapter 27), converted to urea in the liver (Chapter 17), or released as NH3 in the kidney tubular epithelial cells. The last reaction, catalyzed by the enzyme glutaminase, functions in acid-base regulation by neutralizing H+ ions in the urine (Chapter 39). 

Phosphorylation makes sugars anionic the negative charge prevents these sugars from spontaneously leaving the cell by crossing lipid-bilayer membranes. Phosphorylation also creates reactive intermediates that wil more readily form linkages to other molecules. For example, a multipk phosphorylated derivative of ribose plays key roles in the biosyntheses ol purine and pyrimidine nucleotides (p. 712). 

Nucleoside Pyrophosphates. - The synthesis of 8-aryl-3-P-o-ribofuranosylimiazo[2,l-i]purine 5 -phosphates (122) from AMP or ATP has been described. To access these fluorescent nucleotide derivatives, a combination of Kornblum oxidation reaction and imidazole formation was employed. For this conversion, the appropriate adenosine phosphate, present in its free acid form, was treated with p-nitro-acetophenone in DMSO in the presence of DBU. Treatment of a 5-(chloroethyl)-4-(triazole-l-yl)pyrimidine-nucleoside with benzylhydrazine offered the 6,6-bicyclic pyrimido-pyradazin-7-one, the precursor to (123). This triphosphate was used as a substrate for DNA polymerases. ... 

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

In pyrimidine nucleotide synthesis, the carbon and nitrogen atoms are derived from bicarbonate, aspartate, and glutamine. Devise a simple experiment to prove the source of the nitrogen... 

Several types of chemical reduction performed on pyrimidine nucleosides may have application to the pyrimidine nucleotides. For example, sodium amalgam in dilute acetic acid has been used for converting thymidine and 2 -deoxyuridine into a mixture of reduced derivatives, from which... 

The six-membered ring systems 5,6-dihydropyrimidine, 5,6-dihydrouracil and 5,6-dihydrothymine can be hydrolyzed by the enzyme dihydropyrimidinase (E.C. 3.5.2.2), which is involved in the degradation of pyrimidine nucleotides. This widely spread, inducible catabolic enzyme is strictly D-selective in contrast to the L-selective dihydroorotase (E. C. 3.5.2.3), which is involved in the opposite anabolic pathway (see above). Another name often used in the literature for the dihydropyrimidinase is d-hydantoinase, because it is also able to hydrolyze D,L-5-monosubstituted hydantoin derivatives with high activity. Both reactions are shown in Fig. 12.4-7. 

All the pyrimidine nucleotides can proceed to the deoxy compounds as diphosphates, similar to the purines. However, uridine does not occur in DNA therefore, it must be converted to a thymine derivative. This occurs by the following basic pathway CDP is converted to dCDP. This is converted to dCMP, which can produce dUMP. The dUMP is then methylated in the number 5 position, via N5, N10-methylene tetrahydrofolate. This produces deoxythymidine monophosphate (dTMP) and dihydrofolate. The dTMP then can be converted to dTDP and dTTP, which can be incorporated into DNA (Fig. 20.9). 

Uric acid that is produced in man is essentially the product of the action of the enzyme xanthine oxidase on xanthine and hypoxanthine. A tiny amount of uric acid may be ingested as part of the diet, but the great bulk is the result of the action of this enzyme on these two purines. These purines are themselves produced either as a result of the breakdown of cellular material in toto, the turnover of nucleic acids in the cells, or as a result of the intermediary metabolism of various purine nucleotide derivatives. These latter compounds are active in the flow of energy, in methyl group transfer reactions, and as part of the functional molecule of many vitamins. There is direct and indirect evidence that some of the uric acid derives from all these sources. Essentially this evidence consists of the demonstration that other parts of the nucleie acids are found in the urine, such as pyrimidine breakdown products (P9) and methylated purines, which are found only in nucleic acids. There is also isotopic evidence that some labeled purines appear in the urine too quickly after administration of radioactive precursors... 

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