Abstract
The apicoplast organelle of the malaria parasite Plasmodium falciparum contains metabolic pathways critical for liver-stage and blood-stage development. During the blood stages, parasites lacking an apicoplast can grow in the presence of isopentenyl pyrophosphate (IPP), demonstrating that isoprenoids are the only metabolites produced in the apicoplast which are needed outside of the organelle. Two of the isoprenoid biosynthesis enzymes are predicted to rely on iron-sulfur (FeS) cluster cofactors, however, little is known about FeS cluster synthesis in the parasite or the roles that FeS cluster proteins play in parasite biology. We investigated two putative FeS cluster synthesis pathways (Isc and Suf) focusing on the initial step of sulfur acquisition. In other eukaryotes, these proteins can be located in multiple subcellular compartments, raising the possibility of cross-talk between the pathways or redundant functions. In P. falciparum, SufS and its partner SufE were found exclusively the apicoplast and SufS was shown to have cysteine desulfurase activity in a complementation assay. IscS and its effector Isd11 were solely mitochondrial, suggesting that the Isc pathway cannot contribute to apicoplast FeS cluster synthesis. The Suf pathway was disrupted with a dominant negative mutant resulting in parasites that were only viable when supplemented with IPP. These parasites lacked the apicoplast organelle and its organellar genome – a phenotype not observed when isoprenoid biosynthesis was specifically inhibited with fosmidomycin. Taken together, these results demonstrate that the Suf pathway is essential for parasite survival and has a fundamental role in maintaining the apicoplast organelle in addition to any role in isoprenoid biosynthesis.
Highlights
Iron-sulfur (FeS) clusters are ancient protein cofactors found in most organisms
The Plasmodium falciparum genome encodes two distinct FeS cluster synthesis pathways Bioinformatic studies suggest that the genomes of Plasmodium spp. encode both Isc and Suf proteins, including candidate cysteine desulfurases [20,31,32,33,34]
In most eukaryotes the cysteine desulfurases of the Isc and Suf pathways act in complex with the effector proteins Isd11 and SufE, respectively
Summary
Iron-sulfur (FeS) clusters are ancient protein cofactors found in most organisms. FeS clusters are found in a variety of forms, but the most common are cubane 4Fe-4S, cuboidal 3Fe-4S, and binuclear 2Fe-2S clusters [3]. Proteins typically bind these clusters through cysteine residues, other amino acids have been shown to be involved in coordinating the cofactor [1]. The Isc and Suf pathways are the dominant FeS cluster synthesis pathways found in eukaryotes, and are present in bacteria and archaea [5,6]. While the protein components of the Isc and Suf machinery are quite different, both pathways follow the same basic steps of sulfur mobilization, cluster assembly, and cluster transfer (Figure 1)
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