Inhibitory action of marine algae extracts on the Trypanosoma cruzi dihydroorotate dehydrogenase activity and on the protozoan growth in mammalian cells
Inhibitory action of marine algae extracts on the Trypanosoma cruzi dihydroorotate dehydrogenase activity and on the protozoan growth in mammalian cells
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DOI：
10.1016/j.parint.2004.11.001
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发表时间：
2005-03-01
影响因子：
1.9
通讯作者：
Aoki, T
中科院分区：
文献类型：
--
作者：
Nara, T;Kamei, Y;Aoki, T
恰加斯病的病原体克氏锥虫在哺乳动物细胞中复制，依赖于为核酸合成提供必需前体的从头合成嘧啶生物合成途径。原生动物的二氢羊角酸脱氢酶（DHOD）是催化二氢羊角酸生成羊角酸途径的第四个酶，与人类的酶有明显的不同。因此，本研究旨在寻找抗T cruzi DHOD活性的有效抑制剂，并对绿藻、褐藻和红藻制备的甲醇提取物进行了检测。褐藻墨角藻（Fucus evanescens）和龙盆藻（Pelvetia babingtonii）提取物在浓度为50 mug/ml时，重组DHOD活性分别降低了59%和58%。这些提取物对二氢乙酸酯的抑制作用不具有竞争性，其表观K-i值分别为35.3 +/- 5.9和10.3 +/- 4.4马克/毫升。此外，在体外T cruzi-HeLa细胞感染系统中，1杯子/ml浓度的乙醇重组叶莲子提取物和金盏花提取物可显著降低宿主细胞的感染率和每感染细胞的平均寄生虫数量。这些结果表明，F evanescens和P babingtoni在哺乳动物细胞中含有抑制T - cruzi DHOD活性和抑制原生动物感染和增殖的抑制剂。在这两种褐藻中发现抑制剂，并进一步筛选其他海藻，可能有助于发现新的抗锥虫体铅化合物。2004爱思唯尔爱尔兰有限公司版权所有。
Trypanosoma cruzi, the causative agent of Chagas' disease, replicates in mammalian cells and relies on the de novo pyrimidine biosynthetic pathway that supplies essential precursors for nucleic acid synthesis. The protozoan dihydroorotate dehydrogenase (DHOD), the fourth enzyme of the pathway catalyzing production of orotate from dihydroorotate, markedly differs from the human enzyme. This study was thus aimed to search for potent inhibitors against T cruzi DHOD activity, and a number of methanol extracts prepared from green, brown, and red algae were assayed. The extracts from two brown algae, Fucus evanescens and Pelvetia babingtonii, yielded 59 and 58% decrease in the recombinant DHOD activity, respectively, at the concentration of 50 mug/ml. Inhibition by these extracts was noncompetitive with respect to dihydroorotate, with apparent K-i values of 35.3 +/- 5.9 and 10.3 +/- 4.4 mug/ml, respectively. Further, in an in vitro T cruzi-HeLa cell infection system, ethanol-reconstituted E evanescens and R babingtonii extracts at the concentration of 1 mug/ml, respectively, decreased significantly the infection rate of host cells and the average parasite number per infected cell. These results imply that F evanescens and P babingtonii contain inhibitor(s) against the T cruzi DHOD activity and against the protozoan infection and proliferation in mammalian cells. Identification of inhibitor(s) in these two brown algae and further screening of other marine algae may facilitate the discovery of new, anti-trypanosomal lead compounds. (C) 2004 Elsevier Ireland Ltd. All rights reserved.