Role of Heme and Heme-Proteins in Trypanosomatid Essential Metabolic Pathways

Karina E. J. Tripodi,Simón M. Menendez Bravo,Julia A. Cricco

doi:10.4061/2011/873230

Abstract

Around the world, trypanosomatids are known for being etiological agents of several highly disabling and often fatal diseases like Chagas disease (Trypanosoma cruzi), leishmaniasis (Leishmania spp.), and African trypanosomiasis (Trypanosoma brucei). Throughout their life cycle, they must cope with diverse environmental conditions, and the mechanisms involved in these processes are crucial for their survival. In this review, we describe the role of heme in several essential metabolic pathways of these protozoans. Notwithstanding trypanosomatids lack of the complete heme biosynthetic pathway, we focus our discussion in the metabolic role played for important heme-proteins, like cytochromes. Although several genes for different types of cytochromes, involved in mitochondrial respiration, polyunsaturated fatty acid metabolism, and sterol biosynthesis, are annotated at the Tritryp Genome Project, the encoded proteins have not yet been deeply studied. We pointed our attention into relevant aspects of these protein functions that are amenable to be considered for rational design of trypanocidal agents.

Highlights

Trypanosomes are parasitic protists that cause significant human and animal diseases worldwide [1], among which it is important to highlight the species relevant for human health, such as sleeping sickness or African trypanosomiasis (Trypanosoma brucei), Chagas’ disease or American trypanosomiasis (Trypanosoma cruzi), and leishmaniasis (Leishmania spp.)
Trypanosomatids are under varying nutritional pressures during their life cycles; they must adapt their metabolism to different environments
Heme biosynthesis is absent from trypanosomes, and L. major possesses the last three enzymes of the pathway, it still needs to import precursors from the host

Summary

Introduction

Trypanosomes are parasitic protists that cause significant human and animal diseases worldwide [1], among which it is important to highlight the species relevant for human health, such as sleeping sickness or African trypanosomiasis (Trypanosoma brucei), Chagas’ disease or American trypanosomiasis (Trypanosoma cruzi), and leishmaniasis (Leishmania spp.). A direct consequence is the environmental changes suffered among their life cycle they have to adapt their metabolism to different nutrient availability [2] Another feature of these parasites is the presence of nutritional requirements for several essential cofactors where heme is included. Heme plays a fundamental role in many cellular processes It is an essential cofactor for proteins involved in oxygen transport and storage (hemoglobin and myoglobin), mitochondrial electron transport (Complex II–IV), drug and steroid metabolism (cytochromes), signal transduction (nitric oxide synthases, soluble guanylate cyclases), and transcription and regulation of antioxidantdefense enzymes. Heme is a regulatory molecule; its cytosolic to nuclear ratio and the absolute amount of its concentration affects gene transcription and translation; the intracellular heme level must be tightly regulated [4, 5] These trypanosomatids are dependent on the uptake of this compound from their hosts. This review will be focused in the presence and role of relevant heme-proteins in trypanosomatids

Heme General Features

III II HA C Q

Heme in the Mitochondrion

Findings

Concluding Remarks