Monophosphates of formycin B and allopurinol riboside: Interactions with leishmanial and mammalian succino-AMP synthetase and GMP reductase☆

Add time:09/05/2019    Source:sciencedirect.com

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 >95% reduction of the incorporation of the radiolabel from [14C]xanthine into ATP and >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.

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