Uracil pyrimidine nucleoside formation

Figure 3. Proposed mechanism of pyrimidine nucleoside formation, a) Structures of the pyrimidine bases uracil, cytosine, and 2-pyrimidinone. Uracil and cytosine are protonated at N1 and therefore do not possess an in-plane lone pair of electrons, whereas 2-pyrimidinone does, b) The lone pair on 2-pyrimidinone nucleophilically attacks Cl of the oxonium sugar intermediate to form the glycosidic bond.

Deoxyuridine and thymidine are substrates for pyrimidine nucleoside phosphorylases, but deoxycytidine (and cytidine) is generally regarded as being inert to phosphorolysis (7) Tarris demonstration of deoxycytidine formation from cytosine in extracts of fish milt is an exception to this generalization (8). Catabolism of C3rtosine nucleosides is initiated by deamination to form uracil nucleosides which can be phosphorolyzed. 

A study of the mechanism of uracil incorporation into uridine phosphates was carried out in the Ehrlich ascites tumor, a tissue which utilized uracil as well as small molecule precimsors for nucleic acid formation (312). Uridine 5 -phosphate (UMP) was formed from uracil, ATP, and ribose 1-phosphate (R-l-P). Uridine was an intermediate in the formation of the nucleotide and was formed by the reaction of uracil and R-l-P with pyrimidine nucleoside phosphorylase (313, 314). Nucleoside kinase reacted the nucleoside with ATP to form UMP. The sequence is ... 

Prior to the definitive experiments of Friedkin and Komberg (see below), early tracer studies with orotate and with nucleoside derivatives of uracil and cytosine had demonstrated that the pyrimidine ring of DNA thymine could be derived from these compounds. In addition, it had become apparent that the methyl group of thymine was derived from one-carbon units at the oxidation level of formaldehyde rather than at the oxidation level of formate formaldehyde and the hydroxymethyl group... 

On the other hand, as seen in this chapter and in earlier chapters, the formation of phosphates of adenine (e.g., AMP, ADP, and ATP), guanidine (e.g., GTP), cytosine (e.g.,cytidine monophosphate [CMP]), uracil (e.g., uridine monophosphate [UMP]), and dTMP have all involved the carbohydrate scaffold as a building block for the formation of the finished heterocyclic base (purine or pyrimidine). It is also important to realize that, as part of nucleotide salvage pathways, it has been found that a family of enzymes collectively known as phosphorylases serves to catalyze reactions between free bases and phosphate esters of carbohydrates (and related compounds). For example, as shown in Scheme 14.13, the generalized enzyme, purine nucleoside phosphorylase (EC 2.4.2.1), catalyzes the conversion of a purine with... 

A 5-carbon sugar—a pentose—synthesized by the body in all animals, including man. Hence, it is not essential in the diet, but in the body ribose plays an important role. When it is joined with pyrimidines—cytosine, thymine, and uracil and purines—adenine and guanine—nucleosides are formed. When phosphoric acid is esterified with the nucleosides, nucleotides are formed. These compounds are then used in the formation of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). The nucleotides of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and adenosine triphosphate (ATP) are compounds that are essential to cellular metabolism. Ribose is also a constituent of the vitamin riboflavin. 

The Biosynthesis of the Pyrimidine Ring begins with aspartic acid and carbamyl phosphate. The latter is an energy-rich compound which reacts with the former to give carbamylaspartic acid. Ring closure consumes ATP and is in principle an acid amide formation (peptide synthesis). The intermediate dihydro-orotic acid is dehydrogenated to orotic acid, probably by action of a flavoprotein. Orotic acid is the key precursor of pyrimidine nucleotides. It reacts with phosphoribosyl pyrophosphate. The removal of pyrophosphate yields the nucleotide of orotic acid, whose enzymic decarboxylation produces uridine 5 -phosphate. Phosphorylation with ATP yields uridine pyrophosphate and, finally, uridine triphosphate. Beside the above pathway, there is the further possibility of converting free uracil and ribose 1-phosphate to the nucleoside and from there with ATP to the nucleotide. 

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