Monophosphates of formycin B and allopurinol riboside. Interactions with leishmanial and mammalian succino-AMP synthetase and GMP reductase.
Formycin B 5'-monophosphate (Form B-MP) and allopurinol riboside 5'-monophosphate ( HPPR -MP) are isomers of IMP that are metabolically produced when Leishmania spp. are incubated with the antileishmanial agents formycin B and allopurinol or allopurinol riboside. The interactions of Form B-MP with succino -AMP synthetase and GMP reductase from both leishmanial and mammalian sources were compared with the data of earlier studies with HPPR -MP. Both analogs could substitute for IMP as a substrate for succino -AMP synthetase isolated from Leishmania donovani. The V'max values of Form B-MP and HPPR -MP were about 1% of the V'max of IMP. Only Form B-MP (and not HPPR -MP) could serve as an alternative substrate for mammalian succino -AMP synthetase. The V'max of Form B-MP was 40% that of IMP. The corresponding analogs of AMP, ADP and ATP were produced when Formycin B was incubated with mouse L cells. The Formycin A residue was incorporated into the cellular RNA. The amount of Formycin A-TP produced (relative to ATP) in mouse L cells was considerably less than that produced in Leishmania spp. Both Form B-MP and HPPR -MP were inhibitors of partially purified GMP reductase from L. donovani. The binding of Form B-MP and HPPR -MP to human GMP reductase was 40- and 100-fold weaker, respectively, than the binding to leishmanial GMP reductase. Pretreatment of promastigotes of L. donovani with either allopurinol or Formycin B resulted in greater than 95% reduction of the incorporation of the radiolabel from [14C]xanthine into ATP and greater than 80% reduction of the incorporation of the label into GTP. The HPPR -MP and Form B-MP present in these cells may have inhibited the leishmanial succino -AMP synthetase and GMP reductase. The analogs had little or no effect on the pool sizes of ATP and GTP of either mouse L cells or L. donovani.
D000265:Adenylosuccinate Synthase; D000493:Allopurinol / Q000031:analogs & derivatives* / Q000378:metabolism; D000586:Amination; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000378:metabolism* / Q000494:pharmacology; D005573:Formycins / Q000378:metabolism* / Q000633:toxicity; D050899:GMP Reductase; D006801:Humans; D007291:Inosine Monophosphate / Q000378:metabolism; D007700:Kinetics; D007739:L Cells / Q000378:metabolism; D007891:Leishmania / Q000201:enzymology*; D008025:Ligases; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D012263:Ribonucleosides / Q000378:metabolism*; D012265:Ribonucleotides / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000981:Antiprotozoal Agents; D005573:Formycins; D012263:Ribonucleosides; D012265:Ribonucleotides; D007291:Inosine Monophosphate; C021683:formycin 5'-phosphate; C034561:formycin B; C041404:allopurinol riboside 5'-monophosphate; D000493:Allopurinol; D009247:NADH, NADPH Oxidoreductases; D050899:GMP Reductase; D008025:Ligases; D000265:Adenylosuccinate Synthase; C021958:allopurinol riboside