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

https://doi.org/10.1016/j.exppara.2012.01.015Get rights and content
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Abstract

Polyamine biosynthesis enzymes are promising drug targets for the treatment of leishmaniasis, Chagas’ 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 μM, 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’s 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 MnA2+ and MnB2+ 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.

Highlights

► Leishmanicidal flavonoids are strong inhibitors of arginase. ► Quercetin interacts with Mn2+ cofactor and with substrate l-arginine at pH 9.5. ► Catechol group of flavonoids donate two hydrogen bonds to Asp141. ► Quercetin is a mixed inhibitor whereas quercitrin and isoquercitrin are uncompetitive.

Keywords

Leishmania
Arginase
Quercetin
Quercitrin
Isoquercitrin
Polyamine

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