Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion
Antileishmanial effect of 3-aminooxy-1-aminopropane is due to polyamine depletion
复制标题
DOI：
10.1128/aac.01055-06
复制
发表时间：
2007-02-01
影响因子：
4.9
通讯作者：
Madhubala, Rentala
中科院分区：
文献类型：
--
作者：
Singh, Sushma;Mukherjee, Angana;Madhubala, Rentala
多胺腐胺、亚精胺和精胺是细胞生长和分化所需的有机阳离子。鸟氨酸脱羧酶（ODC）是多胺生物合成途径中的第一个酶和限速酶，催化鸟氨酸转化为腐胺。由于多胺生物合成途径对内脏利什曼病的病原体杜氏利什曼原虫的生长和存活至关重要，因此抑制该途径是重要的杀利什曼策略。在本研究中，我们首次研究了ODC抑制剂3-氨氧基-1-氨基丙烷（阿帕）对L。donovani。阿帕抑制前鞭毛体在体外和巨噬细胞模型中的无鞭毛体的生长，50%抑制浓度分别为42和5 μ M。然而，阿帕浓度高达200 μ M并不影响巨噬细胞的生存能力。加入腐胺或亚精胺可完全消除阿帕的作用。阿帕诱导L. donovani promastigotes.寄生虫转染的附加型ODC结构，这些ODC过表达者表现出显着的阿帕耐药，并伴随着耐葡萄糖酸锑钠（Pentoclonal），表明ODC过表达锑耐药的作用。葡萄糖酸锑钠耐药的临床分离株也被发现过表达ODC，腐胺和亚精胺水平显着增加。然而，未观察到锥虫硫酮水平升高。ODC在这些临床分离株中的过表达减轻了阿帕的抗增殖作用。总之，我们的结果表明阿帕是一种有效的L。Donovani生长，其杀利什曼病作用是由于抑制ODC。
The polyamines putrescine, spermidine, and spermine are organic cations that are required for cell growth and differentiation. Ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the polyamine biosynthetic pathway, catalyzes the conversion of ornithine to putrescine. As the polyamine biosynthetic pathway is essential for the growth and survival of Leishmania donovani, the causative agent of visceral leishmaniasis, inhibition of the pathway is an important leishmaniacidal strategy. In the present study, we examined for the first time the effects of 3-aminooxy-1-aminopropane (APA), an ODC inhibitor, on the growth of L. donovani. APA inhibited the growth of both promastigotes in vitro and amastigotes in the macrophage model, with the 50% inhibitory concentrations being 42 and 5 mu M, respectively. However, concentrations of APA up to 200 mu M did not affect the viability of macrophages. The effects of APA were completely abolished by the addition of putrescine or spermidine. APA induced a significant decrease in ODC activity and putrescine, spermidine, and trypanothione levels in L. donovani promastigotes. Parasites were transfected with an episomal ODC construct, and these ODC overexpressers exhibited significant resistance to APA and were concomitantly resistant to sodium antimony gluconate (Pentostam), indicating a role for ODC overexpression in antimonial drug resistance. Clinical isolates with sodium antimony gluconate resistance were also found to overexpress ODC and to have significant increases in putrescine and spermidine levels. However, no increase in trypanothione levels was observed. The ODC overexpression in these clinical isolates alleviated the antiproliferative effects of APA. Collectively, our results demonstrate that APA is a potent inhibitor of L. donovani growth and that its leishmaniacidal effect is due to inhibition of ODC.