Purine specific nucleoside hydrolase

Outside the CNS (central nervous system), pyrrole Mannich bases have found utility in other therapeutic areas as well. The Mannich reaction between iminoibitol and 9-deazahypoxanthine took place at the C3 position to provide an A-pyrrolylmethyl substituted iminoribitol as an inhibitor of a purine-specific nucleoside hydrolase. In terms of regiochemistry, this particular Mannich reaction of 9-deazahypoxanthine behaved similarly to indole rather than to pyrrole. The resulting Mannich bases are potential treatment for parasitic infections. 

Figure 5.29 Isoenzyme-specific inhibitors of purine nucleoside hydrolases.

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). 

Few detailed studies have been done on the purine salvage enzymes of procyclic African trypanosomes. Tb. gambiense has high levels of guanine deaminase and lacks adenine and adenosine deaminase activities (8). Tb. brucei, T.b. gambiense and T.b. rhodesiense convert allopurinol into aminopyrazolopyrimidine nucleotides and incorporates these into RNA (49). This indicates that HPRTase, succino-AMP synthetase, and succino-AMP lyase are present. At least three nucleoside cleavage activities are present (Berens, unpublished results) two are hydrolases, of which one is specific for purine ribonucleosides and the other is specific for purine deoxyribonucleosides. The third nucleoside cleavage activity is a methylthioadenosine/adenosine phosphorylase. The adenosine kinase is similar to that of L. donovani (Berens, unpublished results). 

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...

Although AdoHcy hydrolase is not found in bacteria, AdoHcy is cleaved irreversibly to adenine and S-rlbosyl-L-homocystelne by AdoHcy nucleosidase ". This enzyme has been partially purified from E, aoliy and found to catalyze also the hydrolysis of 5 -methy1-thioadenosine to adenine and methylthiorlbose. The enzyme is inactive towards AdoMet and a variety of other purine and pyrimidine nucleosides. The specific activity of AdoHcy nucleosidase is 1000 x greater than that of AdoHcy hydrolase emphasizing the need to remove AdoHcy, a potent inhibitor of reactions which utilize AdoMet as a substrate. 

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