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

Kloehn, J., Harding, C. R. and Soldati‐Favre, D. (2021) Supply and demand – heme synthesis, salvage and utilization by Apicomplexa. FEBS Journal, 288(2), pp. 382-404. (doi: 10.1111/febs.15445) (PMID:32530125)

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: Published
• 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 > School of Infection & Immunity
• Journal Name: FEBS Journal
• Publisher: Wiley
• 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 288(2): 382-404
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
304336		Iron usage in the eukaryotic parasite Toxoplasma gondii	Clare Harding	Wellcome Trust (WELLCOTR)	213455/Z/18/Z	III - Parasitology