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

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 fromde novosynthesis and/or the development of uptake mechanisms to scavenge heme from their host. Recent studies have revealed that heme synthesis is essential forToxoplasma gondiitachyzoites, as well as for the mosquito and liver stages ofPlasmodiumspp. 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. gondiican tolerate the loss of several heme synthesis enzymes at a high fitness cost, while the ferrochelatase is essential for survival. These findings indicate thatT. gondiiis 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 inT. gondiiandPlasmodium 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 fromde novosynthesis or scavenging, to demand by metabolic pathways, including the electron transport chain.

Automated summary

The Apicomplexa phylum relies on heme as cofactor for enzymes, obtaining it through de novo synthesis or uptake mechanisms. Different stages of the parasites have varying heme uptake strategies, with a synthesis pathway spanning three cellular compartments. Loss of certain heme synthesis enzymes is costly, indicating the parasites' ability to salvage heme precursors.