Adenylosuccinate synthetase and adenylosuccinate lyase from Trypanosoma cruzi, Specificity studies with potential chemotherapeutic agents.
Adenylosuccinate (succino-AMP) synthetase and succino-AMP lyase isolated from epimastigotes of Trypanosoma cruzi by chromatography on phosphocellulose. The synthetase was capable of catalyzing the condensation of aspartic acid with IMP and several IMP analogs. The reaction with allopurinol ribonucleotide is of potential chemotherapeutic interest. This analog was slowly converted to its corresponding succino-AMP analog with a Km' of 140 micrometers (cf. IMP at 10 micrometers) and a Vmax' of 0.3 per cent the rate with IMP. The comparable reaction with this analog does not occur with succino-AMP synthetase from a representative mammalian source [T. Spector and R. L. Miller, Biochim. biophys. Acta 455, 509 (1976)]. The protozoal succino-AMP lyase had a broad substrate which was characteristic of this enzyme from many sources. It catalyzed the rapid and efficient cleavage of all the succino-AMP analogs that were produced by succino-AMP synthetase. Thus, these two enzymes appear to be responsible for the selective amination of allopurinol ribonucleotide in T. cruzi. The metabolically produced AMP analog may be the agent or a precursor of the agent that accounts for the anti-growth activity of allopurinol in these organisms. Similar selective amination was observed previously with these enzymes from Leishmania donovani [T. Spector, T. E. Jones and G. B. Elion, J. biol. Chem. 254, 8422 (1979)]. Thiopurinol ribonucleotide was not a substrate of succino-AMP synthetase from T. cruzi, but it was an inhibitor with a K1 = 33 micrometers. Therefore, the weakness of thiopurinol's anti-growth activity with T. cruzi is not due to its inability to inhibit this enzyme.
D000264:Adenylosuccinate Lyase / Q000302:isolation & purification / Q000378:metabolism*; D000265:Adenylosuccinate Synthase / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D007700:Kinetics; D008025:Ligases / Q000378:metabolism*; D008190:Lyases / Q000378:metabolism*; D051381:Rats; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000201:enzymology*
D014344:Trypanocidal Agents; D008190:Lyases; D000264:Adenylosuccinate Lyase; D008025:Ligases; D000265:Adenylosuccinate Synthase