Pyrimidine nucleoside deaminase

After administration of 50 mg/kg, drug serum levels are depleted in an apparently haphazard fashion in relation to body size. The monkey and man metabolize the drug at a rate greater than any other species studied. However, in this instance there is a reasonable explanation for this deviation. Cytosine arabinoside is metabolized to uracil arabinoside under control of a pyrimidine nucleoside deaminase. The enzyme has a unique distribution in tissues and animal... 

Table 18 Distribution of pyrimidine nucleoside deaminase activity in various animal tissues (Adapted from Camiener and Smith [113])...

The naturally occurring nucleoside analogues discussed in this section contain the IV-glycosyl linkage and either purine, pyrimidine, imidazole, diazepin, or indole rings. The purine nucleosides inhibit protein synthesis, RNA and DNA synthesis, and methyltransferases they have antimycoplasmal, antiviral, hypotensive, antifungal, antimycobacterial, and antitumor activities and induce sporulation (1—4). The pyrimidine nucleosides inhibit protein synthesis, virus replication, RNA and DNA synthesis, and cAMP phosphodiesterase. The imidazole nucleosides inhibit nucleic acid synthesis. The diazepin nucleosides inhibit adenosine deaminase (ADA). The indole nucleosides inhibit bacteria, yeast, fungi, and viruses. 

The salvage activities of T. foetus and T. vaginalis also differ (22,77). Unlike T. foetus, the level of uracil PRTase activity is very low. Uracil is converted into uridine by a uridine phosphorylase uridine is then phosphorylated by a uridine phosphotransferase to UMP (Fig. 6.15). Cytidine and thymidine also are converted into their nucleotide monophosphates by phosphotransferase activities. There is no detectable pyrimidine nucleoside kinase activity and the only significant interconversion among salvaged pyrimidines is catalyzed by cytidine deaminase to form uridine. 

Further in vitro studies using a lung cancer cell line (A549) demonslrated that febuxostat (16 xM for 3h) completely inhibited xanthine oxidase activity without affecting the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, pyrimidine -nucleoside phosphorylase, or guanase. ... 

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. 

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... 

Enzymatic deamination of the naturally occurring pteridin-6-yl acyclo C-nucleosides biopterin (615), dictypterin (616), o-neopterin (618), and d-monapterin (620) with pterin deaminase from the slime mold Dictyostelium discoideum caused their conversion to the corresponding lumazin-6-yl 2,4-dioxopyrazino[2,3-d]pyrimidin-6-yl acyclo C-nucleosides biolumazine (672), dictyolumazine (673), D-neolumazine (674), and D-monalumazine (675), respectively (94MI2) (Scheme 174). 

Leucine aminopeptidase is interesting in that its active site contains two zinc atoms which together bind and activate the water molecule [74]. Despite this enzyme containing a dinuclear metal center at its active site, its mechanism, and specifically its mode of proton transfers reactions, appear to follow the general theme established by thermolysin and carboxypeptidase Adenosine deaminase and other members of the family of nucleoside and nucleotide deaminases utilize zinc-bound water as the catalytic nucleophile to displace ammonia from the 6-position of purines or the 4-position of pyrimidines and in all cases display inverse solvent deuterium isotope effects ranging from 0.3 to 0.8 on fec/Kni [75-80]. These effects are reminiscent of those observed for metallopro-teases and have their origins, like those of the proteases, in fractionation factors for the protons of the bound water that are less than one. 

Phosphodiesterases, phosphatases, 5 -nucleotidases, 3 -nucleotidases and phosphotransferases have been discussed in the section on purine breakdown. Some of these enzymes also act on pyrimidine nucleotides, yielding either the nucleoside or the free base. Cytosine deaminases have been found in yeast and E. coli. Cyti-dine and cytidylic acid deaminases are present in extract of most mammalian tissue. The properties of these enzymes are still poorly understood. 

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