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Abstract
Epigallocatechin-3-gallate (EGCG), a dietary polyphenol (flavanol) from green tea, possesses leishmanicidal and antitrypanosomal activity. Mitochondrial damage was observed in Leishmania treated with EGCG, and it contributed to the lethal effect. However, the molecular target has not been defined. In this study, EGCG, (+)-catechin and (−)-epicatechin were tested against recombinant arginase from Leishmania amazonensis (ARG-L) and rat liver arginase (ARG-1). The compounds inhibit ARG-L and ARG-1 but are more active against the parasite enzyme. Enzyme kinetics reveal that EGCG is a mixed inhibitor of the ARG-L while (+)-catechin and (−)-epicatechin are competitive inhibitors. The most potent arginase inhibitor is (+)-catechin (IC50 = 0.8 µM) followed by (−)-epicatechin (IC50 = 1.8 µM), gallic acid (IC50 = 2.2 µM) and EGCG (IC50 = 3.8 µM). Docking analyses showed different modes of interaction of the compounds with the active sites of ARG-L and ARG-1. Due to the low IC50 values obtained for ARG-L, flavanols can be used as a supplement for leishmaniasis treatment.
Highlights
Food polyphenols show bioactivities that contribute to human health [1,2]
In addition to the known antioxidant activity attributed to green tea (2)-epigallocatechin-3-gallate (EGCG), this compound paradoxically contributes to lethal mitochondrial damage in L. (L.) amazonensis [4]
EGCG is a mixed inhibitor, because the intersection point occurred above the i axis in the Dixon plot and below the axis in the Cornish-Bowden plot (Figure 2)
Summary
Food polyphenols show bioactivities that contribute to human health [1,2]. Balanced food intake enriched with polyphenols from vegetables, green tea, wine and fruits can prevent cardiovascular diseases [3]. In addition to the known antioxidant activity attributed to green tea (2)-epigallocatechin-3-gallate (EGCG), this compound paradoxically contributes to lethal mitochondrial damage in L. EGCG is active against Leishmania (Leishmania) donovani, Trypanossoma brucei rhodesiense [5] and Trypanosoma cruzi [6]. PAs have a central role in proliferation, differentiation, and antioxidant mechanisms in Leishmania [8,9]. Antioxidant mechanisms in trypanosomatids use the PA spermidine to synthesize trypanothione. Trypanothione protects the parasite from oxidative stress by promoting the removal of reactive nitrogen species [10], reactive oxygen species [11] and other reactive species produced by the host’s defense system
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