The Role of Apicoplasts in Malaria Parasites

Hundreds of millions of people all over the world suffer from malaria; hence, the millennium struggle to get it under control has pushed researchers to explore a multitude of scientific avenues to try and find any exploitable flaws in the malaria parasite, Plasmodium falciparum. One of the discoveries made is the apicoplast, which is a chloroplast found within this and other apicomplexan parasites. This organelle, a remnant of the photosynthetic ancestor of the parasite, has recently attracted great interest because of its unusual biological pathways and as a potential drug target. Together with its unique origin and metabolic functions, the fact that the apicoplast plays a crucial role in the life cycle of the parasite offers promising avenues for the development of new antimalarial therapies. The article below sheds some light on the multifaceted roles of the apicoplast, why it is an important factor, and its potential in the ongoing battle to squash malaria.

History and Structure of Apicoplast

The apicoplast seems to be an organelle essentially required in Plasmodium falciparum, and its evolutionary history is intriguing. Probably one of the most complex events to have occurred would be that of a secondary endosymbiosis event involving an ancestral eukaryote engulfing a red alga itself, already containing a primary chloroplast from a cyanobacterium. This organelle has lost its photosynthetic capability over time but has retained other vital functions necessary for survival.

The apicoplast is bound by four membranes, an ultra-structural feature that reflects its colorful evolutionary history. The outer two of these membranes are derived from the host membranes of the endomembrane system, while the inner two represent various algal and cyanobacteria membranes. This structure has implications for its function and for the targeting of proteins synthesized in the cytosol and transported into the apicoplast.

Functions of the Apicoplast

The apicoplast performs various critical activities within the malaria parasite’s biology. Therefore, key activities are metabolic pathways absent in the human host, making it an attractive target for antimalarial drugs. One of the most critical functions of apicoplasts is fatty acid synthesis. The apicoplast contains enzymes involved in the type II fatty acid synthesis pathway. The latter is different from the type I fatty acid synthase found in humans. This pathway is required for the synthesis of fatty acids involved in membrane biogenesis and parasite replication. Thus, inhibition of the enzymes in the FASII pathway will disrupt the life cycle of the parasite; therefore, such enzymes could become prime targets for drug development against this infection.

Another critical pathway in the apicoplast is the non-mevalonate pathway of isoprenoid biosynthesis. This pathway produces the isoprenoids, which are dysfunctional molecules involved in electron transport, cell membrane maintenance, and protein prenylation. The fact that this pathway does not exist in humans brings the apicoplast forward as a selective drug target.

Heme and Iron-Sulfur Cluster Biosynthesis: The apicoplast also participates in the biosynthesis of heme and iron-sulfur clusters, two important cofactors in hundreds of different enzymatic reactions. Apicoplast synthesis of heme complements the heme derived from the host erythrocytes to provide adequate amounts to meet the metabolic demands of the parasite. Iron-sulfur clusters play a crucial role in electron transfer reactions and other metabolic processes.

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Apicoplast Protein Targeting

Proteins involved in apicoplast function are resident in the nuclear genome and hence have to be transferred into the organelle. Targeting the organelle is mediated by leader sequences at the N-terminus of precursor proteins consisting of a signal peptide and a transit peptide. A signal peptide targets the protein into the secretory pathway and, after processing, the peptide into the apicoplast.

This rather complicated mechanism of targeting probably occurs due to several successive steps: the recognition and translocation of the precursor protein with the help of a signal recognition particle into the endoplasmic reticulum; processing and transport—the signal peptide gets cleaved off, and the protein is transported via the secretory pathway to the apicoplast; import and maturation—the transit peptide gets cleaved upon entering the apicoplast, and the mature protein becomes functional within the organelle. Understanding and disrupting this process of targeting can open up new avenues for antimalarial drug development.

Drug Target Potential of the Apicoplast

Metabolic pathways unique to the apicoplast, along with its essential functions, make it an attractive target for antimalarial drugs. Several classes of compounds have been identified that specifically target apicoplast functions, thus disrupting the lifecycle of the parasite without affecting the host.

Antibiotics: The action of most of the antibiotics, such as doxycycline and clindamycin, is focused on the prokaryote-like ribosomes of the apicoplast, where they act as protein synthesis inhibitors. Each of these antibiotics acts slowly but kills the parasites, which proves that the apicoplast has a crucial role in the survival of the parasite.

Fosmidomycin and FR-900098: These two drugs act by inhibiting the enzyme DOXP reductoisomerase, responsible for catalyzing the first step of the non-mevalonate pathway of isoprenoid biosynthesis. By targeting this pathway, these drugs effectively disrupt the production of essential isoprenoids.

Triclosan and Thiolactomycin: Triclosan inhibits the enoyl-acyl carrier protein reductase enzyme in the FASII pathway, whereas thiolactomycin acts as an inhibitor of beta-ketoacyl-ACP synthase. These two drugs work by crippling fatty acid synthesis, consequently killing the parasite.

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Conclusion

The apicoplast is a pillar in Plasmodium falciparum biology; it hosts a variety of activities that are essential for the survival of the parasite but are absent in humans. Its unusual origins and the presence of unique metabolic pathways make it an ideal target for novel antimalarial therapies. It is possible to exploit these differences in designing drugs that are potent yet selective, targeting the apicoplast to minimize damage to the host. With rising resistance to the current antimalarial arsenal, the apicoplast offers a promising new frontier in efforts to eliminate malaria.

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