Entamoeba thiol-based redox metabolism: A potential target for drug development

- We summarize our knowledge on the thiol-based redox mechanism in Entamoeba.
- Entamoeba lacks the glutathione system, but possesses a functional thioredoxin system.
- l-Cysteine and S-methyl-l-cysteine serve as the major thiol in Entamoeba.
- Entamoeba exploits l-cysteine, thiazolidine-4-carboxylic acids and thioredoxin system for antioxidative defense.
- Antioxidative defense and redox mechanisms can be viewed as potential drug targets against amebiasis.

Amebiasis is an intestinal infection widespread throughout the world caused by the human pathogen Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its low efficacy against asymptomatic cyst carriers and emergence of resistance in other protozoa with similar anaerobic metabolism. Therefore, identification and characterization of specific targets is urgently needed to design new therapeutics for improved treatment against amebiasis. Toward this goal, thiol-dependent redox metabolism is of particular interest. The thiol-dependent redox metabolism in E. histolytica consists of proteins including peroxiredoxin, rubrerythrin, Fe-superoxide dismutase, flavodiiron proteins, NADPH: flavin oxidoreductase, and amino acids including l-cysteine, S-methyl-l-cysteine, and thioprolines (thiazolidine-4-carboxylic acids). E. histolytica completely lacks glutathione and its metabolism, and l-cysteine is the major intracellular low molecular mass thiol. Moreover, this parasite possesses a functional thioredoxin system consisting of thioredoxin and thioredoxin reductase, which is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In this review, we summarize and highlight the thiol-based redox metabolism and its control mechanisms in E. histolytica, in particular, the features of the system unique to E. histolytica, and its potential use for drug development against amebiasis.