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

• Published in: The FEBS journal 2021-01, Vol.288 (2), p.382-404
• Main Authors: Kloehn, Joachim, Harding, Clare R., Soldati‐Favre, Dominique
• Format: Article
• Language: English
• Subjects: Apicomplexa; Artemisinin; Cryptosporidiosis; Cytochromes; drug resistance; Electron transport; Electron transport chain; Enzymes; Erythrocytes; Ferrochelatase; Heme; heme synthesis; heme uptake; Malaria; Metabolic pathways; metabolism; Mosquitoes; Parasites; Plasmodium species; Scavenging; Synthesis; Tachyzoites; Therapeutic targets; Toxoplasma gondii; Toxoplasmosis; Vector-borne diseases
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15445

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 cofactor 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. Heme is a ubiquitous cofactor essential for most organisms. The human pathogens Toxoplasma gondii and Plasmodium spp. can salvage heme or its intermediates from their host, but largely rely on its de novo synthesis utilizing an unusual heme synthesis pathway, which spans across three subcellular compartments. This review discusses our understanding of heme acquisition in apicomplexans, its role in metabolism, and in the activation of the antimalarial drug artemisinin (ART).