Inhibition of Leishmania (Leishmania) amazonensis and rat arginases by green tea EGCG, (+)-catechin and (-)-epicatechin: a comparative structural analysis of enzyme-inhibitor interactions

PLoS One. 2013 Nov 8;8(11):e78387. doi: 10.1371/journal.pone.0078387. eCollection 2013.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / chemistry
  • Arginase / antagonists & inhibitors*
  • Arginase / chemistry*
  • Catechin / analogs & derivatives*
  • Catechin / chemistry*
  • Enzyme Inhibitors / chemistry*
  • Leishmania / enzymology*
  • Liver / enzymology*
  • Molecular Docking Simulation*
  • Protozoan Proteins / antagonists & inhibitors*
  • Rats

Substances

  • Anticarcinogenic Agents
  • Enzyme Inhibitors
  • Protozoan Proteins
  • Catechin
  • epigallocatechin gallate
  • Arginase

Grants and funding

This research was supported by grant #012/17059-5, São Paulo Research Foundation (FAPESP). MBGR and LCM received fellowships from FAPESP and PIBITI-RUSP (Programa Institucional de Bolsas de Iniciação Científica em Desenvolvimento Tecnológico e Inovação-Reitoria da Universidade de São Paulo), respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.