Trypanothione: a unique bis-glutathionyl derivative in trypanosomatids

Biochim Biophys Acta. 2013 May;1830(5):3199-216. doi: 10.1016/j.bbagen.2013.01.013. Epub 2013 Feb 8.

Abstract

Background: Trypanosomatids are early-diverging eukaryotes devoid of the major disulfide reductases - glutathione reductase and thioredoxin reductase - that control thiol-redox homeostasis in most organisms. These protozoans have evolved a unique thiol-redox system centered on trypanothione, a bis-glutathionyl conjugate of spermidine. Notably, the trypanothione system is capable to sustain several cellular functions mediated by thiol-dependent (redox) processes.

Scope of review: This review provides a summary of some historical and evolutionary aspects related to the discovery and appearance of trypanothione in trypanosomatids. It also addresses trypanothione's biosynthesis, physicochemical properties and reactivity towards biologically-relevant oxidants as well as its participation as a cofactor for metal binding. In addition, the role of the second most abundant thiol of trypanosomatids, glutathione, is revisited in light of the putative glutathione-dependent activities identified in these organisms.

Major conclusions: Based on biochemical and genome data, the occurrence of a thiol-redox system that is strictly dependent on trypanothione appears to be a feature unique to the order Kinetoplastida. The properties of trypanothione, a dithiol, are the basis for its unique reactivity towards a wide diversity of oxidized and/or electrophilic moieties in proteins and low molecular weight compounds from endogenous or exogenous sources. Novel functions have emerged for trypanothione as a potential cofactor in iron metabolism.

General significance: The minimalist thiol-redox system, developed by trypanosomatids, is an example of metabolic fitness driven by the remarkable physicochemical properties of a glutathione derivative. From a pharmacological point of view, such specialization is the Achilles' heel of these ancient and deadly parasites. This article is part of a Special Issue entitled Cellular functions of glutathione.

Publication types

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

MeSH terms

  • Animals
  • Glutathione / analogs & derivatives*
  • Glutathione / metabolism*
  • Humans
  • Oxidants / metabolism
  • Oxidation-Reduction
  • Spermidine / analogs & derivatives*
  • Spermidine / metabolism
  • Sulfhydryl Compounds / metabolism
  • Trypanosomatina / metabolism*

Substances

  • Oxidants
  • Sulfhydryl Compounds
  • trypanothione
  • Glutathione
  • Spermidine