Uridine hydrolase

Several nucleoside hydrolases have been described. A hydrolase purified from baker s yeast (79) has been found which specifically degrades uridine to uracil and n-ribose. Another nucleoside hydrolase also purified from yeast splits guanoane, adenosine, inosine, xanthosine, nicotinamide riboside, and a group of synthetic unnatural riborides. A highly specific uridine hydrolase is found in yeast, and a nucleoride hydrolase has been described in Lactobacillus pentosus which degrades both purine and pyrimidine nucleosides (74)- A nonspecific hydrolase as well as a i cific inosine hydrolase have been purified from fish muscle (76). The spores of BaciUus eereus contain a heat-stable hydrolase which can cleave adenosine and inosine (76, 77). Finally, a riboside hydrolase of broad spedfidty which attacks only 9-ribofuranosides has been purified from extracts of Ladobacil-lus delbrueckii (72, 78). 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Thie enzyme [EC 3.2.2.1], also known as inosine-uridine preferring nucleoside hydrolase and lU-nucleoside hydrolase, catalyzes the hydrolysis of an A-o-ribosylpurine to produce a purine and D-ribose. 

Ribonuclease Ua digestion of ApU has revealed reduced hydrolase activity in the second step of RNase U2 action (30). When 87.4% of ApU was readily degraded to produce uridine and adenosine 2, 3 -cyclic phosphate, no 3 -adenylic acid was detected. After exhaustive degradation of ApU, hydrolysis of adenosine 2, 3 -cyclic phosphate occurred and 3 -adenylic acid gradually appeared. 

The antiviral action of vidarabine is completely confined to DNA viruses. Vidarabine inhibits viral DNA synthesit En/ymes within the cell phosphorylate vidarabine to thetn-phosphate, which competes with deoxyadenosine triphov phatc for viral DNA polymerase. Vidtirabine triphasphatcit also incorporated into cellular and viral DNA. where iiait as a chain terminator. The triphosphate form of vidarabine also inhibits a set of en/.ymes that are involved in methyb-lion of uridine to thymidine ribonucicoside reducla.se. RN.A polyadenylase. and 5-adenosylhomocy.slcine hydrolase. 

Similarly, inosine hydrolysis catalyzed by inosine-uridine-specific nucleoside hydrolase (lU-NH) was modeled by ad hoc methods with Ui q = 0.19 and Nu = 0.005/ but has been reanalyzed recently using structure interpolation, which gives a TS structure with Xlg — and (unpublished results). It... 

FIG. 6.13 Mammalian pyrimidine salvage and interconversion pathways. Enzymes listed in Figs 6.13-6.17 are as follows (1) deoxyCMP deaminase (2) thymidylate synthase (3) ribonucleotide reductase (4) deoxyuridine triphosphatase (5) CTP synthetase (6) nucleotide kinase (7) deoxyTMP kinase (8) nucleotide diphosphokinase (9) non-specific phosphatase or nucleotidase (10) cytidine kinase (11) pyrimidine phos-phorylase or hydrolase (12) uracil PRTase (13) cytidine deaminase (14) thymidine kinase (15) cytidine phosphotransferase (16) uridine phosphotransferase (17) thymidine phosphotransferase (18) deoxyribo-nucleotide phosphotransferase (19) cytosine PRTase. 

Beacham, I.R., Kahana, R., Levy, L. and Yagil, E. (1 973) Mutants of Escherichia coii K-12 cryptic, or deficient in 5 -nucleotidase (uridine diphosphate-sugar hydrolase) and 3 -nucleotidase (cyclic phosphodiesterase) activity.yourna/ of Bacterioiogy 11 5, 957-964. 

In contrast, 5 -NT is an enzyme that has been known since the 1960s, but its chemistry has not been examined as extensively. 5 -NT was initially characterized as a periplasmic UDP-sugar hydrolase. As such, its likely function is to cleave UDP-glucose in the environment into uridine,... 

Fig. 23.1. Pyrimidine pathways Pathways for the de novo synthesis, interconversion, and breakdown of pyrimidine ribonucleotides, indicating their metabolic importance as the essential precursors of the pyrimidine sugars and, with purines, of DNA and RNA. Note that in contrast to purines salvage takes place at the nucleoside not the base level in human cells and pyrimidine metabolism normally lacks any detectable end-product. The importance of this network is highlighted by the variety of clinical symptoms associated with the possible enzyme defects indicated. 23.10, Uridine monophosphate synthase (UMPS), 23.11a, uridine monophosphate hydrolase 1 (UMPHl), 23.12, thymidine phosphorylase (TP), 23.13, dihydropyrimidine dehydrogenase (DPD), 23.14, dihydropyrimidine amidohydrolase (DHP), 23.15, y -ureidopropionase (UP) (23.11b, UMPH superactivity specific to fibroblasts is not shown). CP, carbamoyl phosphate. The pathological metabolites used as specific markers in differential diagnosis are highlighted...

The possibility that a component of this "adenosine 5 -aldehyde" mixture is the actual inhibitor was supported by the following observations (1) the chemically stable 7b was not an inhibitor of AdoHcy hydrolase (2) Ado and Hey were rapidly converted into AdoHcy by AdoHcy hydrolase, but 7b and Hey gave no detected AdoHcy (3) the chemically stable sulfones 18 and 20 derived firom 10b were not inhibitors (4) the uridine analogues of 10b [5 (R/S)-fluoro-5 -5-(4-methoxyphenyl)-5 -thiouridine] w e not inhibitors. 

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