Action of tubercidin and other adenosine analogs on Schistosoma mansoni schistosomules.
The incorporation of the radiolabeled adenosine analogs tubercidin, formycin A, 9-deaza-adenosine, and adenine arabinoside into nucleotides of Schistosoma mansoni schistosomules was studied in vitro. Of the four analogs, only tubercidin and formycin A were incorporated into the nucleotide pool, at rates respectively one-tenth and one-fiftieth the rate of adenosine incorporation. Tubercidin inhibited schistosomule motility in vitro with an approximate IC50 value of 1 microM, whereas formycin A exerted no visible effect even when more of it than of tubercidin was incorporated into the nucleotides and nucleic acids. Formycin A thus acts like a nontoxic adenosine analog. 7-Deaza-adenine, the purine base of tubercidin, was not incorporated into nucleotides. 7-Deaza-adenine, 9-deaza-adenosine, and adenine arabinoside all had no effect on schistosomule motility at concentrations up to 100 microM. Formycin A blocked the incorporation of tubercidin and of adenosine with equal effectiveness, as did p-nitrobenzyl-6-mercaptopurine ribonucleoside, a specific inhibitor of nucleoside transport in many mammalian cells. Thus, formycin A, tubercidin, and adenosine appear to have a common mechanism of cellular uptake. The significant levels of adenosine phosphorylase and adenine phosphoribosyl transferase activity found in schistosomule extracts suggests that most of the transported adenosine is converted to adenine before conversion to AMP. The levels of adenosine kinase and tubercidin kinase, while low, can more than account for the rate of tubercidin incorporated into intact schistosomules. The kinase(s) may also represent a minor pathway for direct adenosine incorporation. It may have a rather unusual substrate specificity because it is able to recognize adenosine, tubercidin, and formycin A as substrates, but not 9-deaza-adenosine or adenine arabinoside.
D000241:Adenosine / Q000378:metabolism; D000248:Adenosine Kinase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D005573:Formycins / Q000378:metabolism / Q000494:pharmacology*; D009068:Movement / Q000187:drug effects; D009711:Nucleotides / Q000096:biosynthesis; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D013379:Substrate Specificity; D014372:Tubercidin / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D014740:Vidarabine / Q000378:metabolism / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D005573:Formycins; D009711:Nucleotides; D012263:Ribonucleosides; D000249:Adenosine Monophosphate; C034550:formycin; C038031:9-deazaadenosine; C019603:adenosine phosphorylase; D011683:Purine-Nucleoside Phosphorylase; D000248:Adenosine Kinase; D014740:Vidarabine; D000241:Adenosine; D014372:Tubercidin