The leishmanicidal flavonols quercetin and quercitrin target Leishmania (Leishmania) amazonensis arginase

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• 作者：Edson Roberto da Silva^a ; ^{edsilva@usp.br} ; Claudia do Carmo Maquiaveli^b ; ^{cmaquiaveli@usp.br} ; Prislaine Pupolin Magalhã ; es^c ; ^{pupolin@usp.br}
• 关键词：Leishmania ; Arginase ; Quercetin ; Quercitrin ; Isoquercitrin ; Polyamine
• 刊名：Experimental Parasitology
• 出版年：2012
• 期刊代码：99_00144894
• 类别：imm
• 出版时间：March, 2012
• 卷：130
• 期：3
• 页码：183-188
• 文件大小：563 K

摘要

Polyamine biosynthesis enzymes are promising drug targets for the treatment of leishmaniasis, Chagas鈥?disease and African sleeping sickness. Arginase, which is a metallohydrolase, is the first enzyme involved in polyamine biosynthesis and converts arginine into ornithine and urea. Ornithine is used in the polyamine pathway that is essential for cell proliferation and ROS detoxification by trypanothione. The flavonols quercetin and quercitrin have been described as antitrypanosomal and antileishmanial compounds, and their ability to inhibit arginase was tested in this work. We characterized the inhibition of recombinant arginase from Leishmania (Leishmania) amazonensis by quercetin, quercitrin and isoquercitrin. The IC₅₀ values for quercetin, quercitrin and isoquercitrin were estimated to be 3.8, 10 and 4.3 渭M, respectively. Quercetin is a mixed inhibitor, whereas quercitrin and isoquercitrin are uncompetitive inhibitors of L. (L.) amazonensis arginase. Quercetin interacts with the substrate l-arginine and the cofactor Mn²⁺ at pH 9.6, whereas quercitrin and isoquercitrin do not interact with the enzyme鈥檚 cofactor or substrate. Docking analysis of these flavonols suggests that the cathecol group of the three compounds interact with Asp129, which is involved in metal bridge formation for the cofactors and in the active site of arginase. These results help to elucidate the mechanism of action of leishmanicidal flavonols and offer new perspectives for drug design against Leishmania infection based on interactions between arginase and flavones.