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

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 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.

Biosynthetic heme of malaria parasite induces cerebral pathogenesis by regulating hemozoin formation and griseofulvin can prevent cerebral malaria

“…Malaria parasite scavenges stearic acid (SA) from plasma and converts it into OA by ER-localized Δ9-desaturase (stearoyl-CoA 9-desaturase). The cis double bond formation in OA requires heme since it utilizes the electrons transferred by cytochrome b5 from NADH cytochrome b5 reductase 61, 62 . In vitro 14 C-SA radiolabelling and the separation of unsaturated FAMEs prepared from FCKO total parasites and FVs showed almost 80-90% decrease in the levels of OA methyl ester (OAME) in comparison to WT (Fig.…”

“…Importantly, we show drastic reduction in OA synthesis of FCKO parasites with not much change in phospholipids or neutral lipids, suggesting an alteration in the degree of lipid unsaturation that can affect Hz formation. OA synthesis in malaria parasite is catalysed by a heme-dependent, ER-localized, Δ9-desaturase and it does not occur in uninfected RBCs 61, 62 . Our results suggest the specific role of de novo heme in OA synthesis that cannot be compensated by host Hb-heme.…”

“…The copyright holder for this preprint this version posted April 27, 2021. ; https://doi.org/10.1101/2021.04.27.441715 doi: bioRxiv preprint change in phospholipids or neutral lipids, suggesting an alteration in the degree of lipid unsaturation that can affect Hz formation. OA synthesis in malaria parasite is catalysed by a heme-dependent, ER-localized, ∆9-desaturase and it does not occur in uninfected RBCs 61,62 .…”

Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility

“…Modulation of heme biosynthesis in cancer cells has similarly been found to alter their susceptibility to ART 57 . By contrast, heme biosynthesis pathways are dispensable for P. falciparum growth during blood stages, although this pathway appears to be necessary during the mosquito stages 87,88 . Although de novo heme synthesis is dispensable for blood-stage P. falciparum, the components of this pathway are still expressed, and studies using radiolabeled substrates for heme biosynthesis have shown that the process remains active [89][90][91] .…”

Using Diatom and Apicomplexan Models to Study the Heme Pathway of Chromera velia

“…While the tetrapyrrole pathway is almost universally present, the subcellular distribution of the enzymes differs widely across the eukaryotic biodiversity. Location corresponds to the trophic strategy of the organism, cellular demand for the final products of the pathway, the evolutionary origin of the enzyme, and the need for tight regulation of the pathway [ 6 , 7 , 8 , 9 , 10 ].…”