Pyrimidine phosphorylase

The bromide (2a) reacted smoothly with 2,4-diethoxy-5-methylpyrimi-dine to give, after de-ethylation and deacylation, l-(2-deoxy-/ -D-arabino-hexopyranosyl)thymine (3) (15). The new nucleoside (3) is the first truly competitive inhibitor of a pyrimidine phosphorylase (7), that is, it inhibits the phosphorylase, yet is not a substrate for the enzyme. It was recently shown that 3 enhances the incorporation of 2 -deoxy-5-iodouridine in vivo in cats (8). 

Pyrimidine phosphorylase can use all of the pyrimidines but has a preference for uracil and is sometimes called uridine phosphorylase. The phosphorylase uses cytosine fairly well but has a very, very low affinity for thymine therefore, a ribonucle-oside containing thymine is almost never made in vivo. A second phosphorylase, thymine phosphorylase, has a much higher affinity for thymine and adds a deoxyri-bose residue (see Fig. 41.17). 

Tlqrmidine phosphorylase has been purified from horse liver (67). The enzyme is reactive with uracil and thymine riboddes and deoxy-riboddes. Another pyrimidine phosphorylase, uridine phosphorylase (68), purified from a strain of E. coli, catalyzes the cyntheds and degradation of uracil ribodde (69). The enzyme is also found in liver (70). 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

A class of compounds, called immucillins <2003BBR917>, are potent transition-state analogs of purine nucleoside phosphorylase. As such these pyrrolo[3,2-4 pyrimidines have been the target of much exploration. 

Ultraviolet (UV) spectroscopy does not tend to be the method of choice for structure determination, but a list of UV absorptions was given in the review by Knowles <1996CHEC-II(7)489>. Fluorescence properties and triplet yields of [l,2,3]triazolo[4,5-r/ pyridazines in various solvents have been reported <2002JPH83>. These heterocyclic systems were found to be photochemically very stable. In a recent paper, Wierzchowski et al. studied the fluorescence emission properties of 8-azaxanthine ([l,2,3]triazolo[4,5-r/ pyrimidine-5,7-dione) and its A -alkyl derivatives at various pH s <2006JPH276>. For the 8-azaxanthines, an important characteristic of emission spectra in aqueous solutions was the unusually large Stokes shift. Since 8-azaxanthine is a substrate for purine nucleoside phosphorylase II from Escherichia coli, the reaction is now monitored fluorimetrically. The fluorescence properties of [l,2,3]triazolo[4,5-r/ -pyrimidine ribonucleosides were earlier described by Seela et al. <2005HCA751>. 

Table 7.1.4 Concentration range of purine and pyrimidine metabolites in urine (pmol/mmol creatinine) from patients. ADA Adenosine deaminase, APRT adenine phosphoribosyltransferase, ASA adenylosuccinate lyase, DHP dihydropyrimidinase, DPD dihydropyrimidine dehydrogenase, HGPRT hypoxanthine-guanine phosphoribosyltransferase, PNP purine nucleoside phosphorylase, TP thymidine phosphorylase, UMPS uridine monophosphate synthase, / -UP fi-ureidopropionase... 

Just as orotic acid is converted to a ribonucleotide in step e of Fig. 25-14, other free pyrimidine and purine bases can react with PRPP to give monoribonucleotides plus PP . The reversible reactions, which are catalyzed by phosphoribosyltransferases (ribonucleotide pyrophosphorylases), are important components of the salvage pathways by which purine and pyrimidine bases freed by the degradation of nucleic acids are recycled.273 However, thymine is usually not reused. Thymine will react with deoxribose 1-P to form thymidine plus inorganic phosphate (thymidine phosphorylase), and thymidine is rapidly... 

Allosteric Enzymes Typically Exhibit a Sigmoidal Dependence on Substrate Concentration The Symmetry Model Provides a Useful Framework for Relating Conformational Transitions to Allosteric Activation or Inhibition Phosphofructokinase Allosteric Control of Glycolysis Is Consistent with the Symmetry Model Aspartate Carbamoyl Transferase Allosteric Control of Pyrimidine Biosynthesis Glycogen Phosphorylase Combined Control by Allosteric Effectors and Phosphorylation... 

Pyrimidine nucleosides and their analogs as uridine phosphorylase inhibitors and potential chemotherapeutic agents 91CLY171. 

Nucleoside phosphorylase Purines + Pyrimidines Ribose I-phosphate... 

A phosphorylase from Escherichia coli has been purified it is specific for 2-deoxy-D-ribosyl phosphate, but can use uracil, 2-thiouracil, 5-amino-uracil, 5-bromouracil, and 2-thiothymine as a pyrimidine. Deaminases of adenosine, 2-deoxyadenosine, cytidine, and 2-deoxycytidine have been detected in Escherichia coli. 

Nucleoside phosphorylases catalyze the reversible phosphorolysis in nucleosides and the transferase reaction involving purine or pyrimidine bases [42]. Scheme... 

Pyrimidines derived from dietary or endogenous sources are salvaged efficiently in mammalian systems. They are converted to nucleosides by nucleoside phosphorylases and then to nucleotides by appropriate kinases. 

Cytidine so formed is converted to uridine by cy-tidine aminohydrolase, while uridine and thymidine are converted to free bases by pyrimidine nucleoside phosphorylase. 

Purine nucleosides are cleaved by the action of purine nucleoside phosphorylase with the liberation of ribose 1-phosphate (Kl, PI). The enzyme is apparently specific for purines. The material from erythrocytes catalyzes the phosphorolysis of purine but not pyrimidine nucleosides (T6.) Purine phosphorylase activity is found widespread in nature and in many animal tissues (FIO). Friedkin and Kalckar investigated an enzyme capable of cleaving purine deoxynucleosides to the aglycone and deoxy-ribose 1-phosphate. They concluded that the enzyme was identical to that which splits purine ribonucleosides (F8, F9). This enzyme is capable of degrading inosine, xanthosine, and guanosine to forms readily attacked by other enzymes. In so doing, it permits living cells to retain the ribose and deoxyribose moieties. 

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