Spector T, Jones T E, LaFon S W, Nelson D J, Berens R L, Marr J J
Biochem Pharmacol. 1984 May 15;33(10):1611-7. doi: 10.1016/0006-2952(84)90282-x.
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.
5'-单磷酸间型霉素B（间型霉素B - MP）和5'-单磷酸别嘌呤醇核糖苷（HPPR - MP）是次黄嘌呤核苷酸（IMP）的异构体，当利什曼原虫属与抗利什曼原虫药物间型霉素B、别嘌呤醇或别嘌呤醇核糖苷一起孵育时，它们会通过代谢产生。将间型霉素B - MP与来自利什曼原虫和哺乳动物的琥珀酸 - AMP合成酶及GMP还原酶的相互作用，与早期关于HPPR - MP的研究数据进行了比较。两种类似物都可以替代IMP作为从杜氏利什曼原虫分离出的琥珀酸 - AMP合成酶的底物。间型霉素B - MP和HPPR - MP的V'max值约为IMP的V'max的1%。只有间型霉素B - MP（而非HPPR - MP）可以作为哺乳动物琥珀酸 - AMP合成酶的替代底物。间型霉素B - MP的V'max为IMP的40%。当间型霉素B与小鼠L细胞一起孵育时，会产生AMP、ADP和ATP的相应类似物。间型霉素A残基被掺入细胞RNA中。小鼠L细胞中产生的间型霉素A - TP（相对于ATP）的量远少于利什曼原虫属中产生的量。间型霉素B - MP和HPPR - MP都是杜氏利什曼原虫部分纯化的GMP还原酶的抑制剂。间型霉素B - MP和HPPR - MP与人GMP还原酶的结合分别比利什曼原虫GMP还原酶的结合弱40倍和100倍。用别嘌呤醇或间型霉素B预处理杜氏利什曼原虫前鞭毛体，导致[14C]黄嘌呤的放射性标记掺入ATP的量减少超过95%，掺入GTP的量减少超过80%。这些细胞中存在的HPPR - MP和间型霉素B - MP可能抑制了利什曼原虫的琥珀酸 - AMP合成酶和GMP还原酶。这些类似物对小鼠L细胞或杜氏利什曼原虫的ATP和GTP库大小几乎没有影响。
