Nelson D J, Bugge C J, Elion G B, Berens R L, Marr J J
J Biol Chem. 1979 May 25;254(10):3959-64.
Leishmania donovani and Leishmania braziliensis grown in culture formed millimolar concentrations of allopurinol ribonucleoside 5'-monophosphate from [6-14C]allopurinol. In addition, allopurinol 1-ribonucleoside, oxipurinol riboside 5'-monophosphate, and three new metabolites of allopurinol, namely, 4-aminopyrazolo(3,4-d)pyrimidine ribonucleoside 5'-monophosphate and the corresponding di- and triphosphates (1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-diphosphate and 1-ribosyl 4-aminopyrazolo(3,4-d)pyrimidine 5'-triphosphate) were identified in the parasitic cells. They were formed via a unique amination reaction from 1-ribosyl allopurinol 5'-phosphate, analogous to the conversion of IMP to AMP. [6-14C]Allopurinol was incorporated into RNA of L. donovani in the form of 4-aminopyrazolo(3,4-d)pyrimidine. Adenine reversed the growth inhibition of allopurinol and prevented its metabolism to all of the ribonucleotide metabolites. L. donovani was 2- to 4-fold more active in its metabolism of allopurinol to ribonucleotides than L. braziliensis. 4-Aminopyrazolo(3,4-d)pyrimidine inhibited cell growth and resulted in high intracellular levels of 1-ribosyl allopurinol 5'-phosphate and smaller amounts of the 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides. The metabolism of allopurinol to 4-aminopyrazolo(3,4-d)pyrimidine ribonucleotides and its resultant cytotoxicity occurs in these parasitic protozoans, but not in mammalian cells.
在培养物中生长的杜氏利什曼原虫和巴西利什曼原虫能将[6-¹⁴C]别嘌呤醇转化为毫摩尔浓度的别嘌呤醇核糖核苷5'-单磷酸。此外，还在寄生细胞中鉴定出了别嘌呤醇1-核糖核苷、氧嘌呤醇核糖核苷5'-单磷酸以及别嘌呤醇的三种新代谢产物，即4-氨基吡唑并[3,4-d]嘧啶核糖核苷5'-单磷酸及其相应的二磷酸和三磷酸（1-核糖基4-氨基吡唑并[3,4-d]嘧啶5'-二磷酸和1-核糖基4-氨基吡唑并[3,4-d]嘧啶5'-三磷酸）。它们是通过1-核糖基别嘌呤醇5'-磷酸的独特胺化反应形成的，类似于肌苷酸向腺苷酸的转化。[6-¹⁴C]别嘌呤醇以4-氨基吡唑并[3,4-d]嘧啶的形式掺入杜氏利什曼原虫的RNA中。腺嘌呤可逆转别嘌呤醇对生长的抑制作用，并阻止其代谢为所有核糖核苷酸代谢产物。杜氏利什曼原虫将别嘌呤醇代谢为核糖核苷酸的活性比巴西利什曼原虫高2至4倍。4-氨基吡唑并[3,4-d]嘧啶抑制细胞生长，并导致细胞内1-核糖基别嘌呤醇5'-磷酸水平升高，而4-氨基吡唑并[3,4-d]嘧啶核糖核苷酸的量较少。别嘌呤醇向4-氨基吡唑并[3,4-d]嘧啶核糖核苷酸的代谢及其产生的细胞毒性在这些寄生原生动物中发生，但在哺乳动物细胞中不发生。
