Supply and demand – heme synthesis, salvage and utilization by Apicomplexa

Kloehn, J., Harding, C. R. and Soldati‐Favre, D. (2020) Supply and demand – heme synthesis, salvage and utilization by Apicomplexa. FEBS Journal, (doi: 10.1111/febs.15445) (PMID:32530125) (Early Online Publication)

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Abstract

The Apicomplexa phylum groups important human and animal pathogens that cause severe diseases, encompassing malaria, toxoplasmosis and cryptosporidiosis. In common with most organisms, apicomplexans rely on heme as co‐factor for several enzymes, including cytochromes of the electron transport chain. This heme derives from de novo synthesis and/or the development of uptake mechanisms to scavenge heme from their host. Recent studies have revealed that heme synthesis is essential for Toxoplasma gondii tachyzoites, as well as for the mosquito and liver stages of Plasmodium spp . In contrast, the erythrocytic stages of the malaria parasites rely on scavenging heme from the host red blood cell. The unusual heme synthesis pathway in Apicomplexa spans three cellular compartments and comprises enzymes of distinct ancestral origin, providing promising drug targets. Remarkably given the requirement for heme, T. gondii can tolerate the loss of several heme synthesis enzymes at a high fitness cost, while the ferrochelatase is essential for survival. These findings indicate that T. gondii is capable of salvaging heme precursors from its host. Furthermore, heme is implicated in the activation of the key antimalarial drug artemisinin. Recent findings established that a reduction in heme availability corresponds to decreased sensitivity to artemisinin in T. gondii and Plasmodium falciparum , providing insights into the possible development of combination therapies to tackle apicomplexan parasites. This review describes the microeconomics of heme in Apicomplexa; from supply, either from de novo synthesis or scavenging, to demand by metabolic pathways, including the electron transport chain.

Item Type:Articles
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harding, Dr Clare
Authors: Kloehn, J., Harding, C. R., and Soldati‐Favre, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:FEBS Journal
Publisher:Wiley-Blackwell Publishing Ltd.
ISSN:1742-464X
ISSN (Online):1742-4658
Published Online:12 June 2020
Copyright Holders:Copyright © 2020 Federation of European Biochemical Societies
First Published:First published in FEBS Journal 2020
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
304336Iron usage in the eukaryotic parasite Toxoplasma gondiiClare HardingWellcome Trust (WELLCOTR)213455/Z/18/ZIII - Parasitology