Critical role for isoprenoids in apicoplast biogenesis by malaria parasites
Autor: | Russell P. Swift, Sean T. Prigge, Krithika Rajaram, John Alan Maschek, Amanda Mixon, Paul A. Sigala, Megan Okada |
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Rok vydání: | 2021 |
Předmět: |
Plasmodium falciparum
Isopentenyl pyrophosphate Protozoan Proteins Biology Apicoplasts General Biochemistry Genetics and Molecular Biology Polyprenols chemistry.chemical_compound Prenylation Organelle Animals Parasites Malaria Falciparum Apicoplast ATP synthase General Immunology and Microbiology Terpenes General Neuroscience General Medicine biology.organism_classification Cell biology chemistry Transfer RNA biology.protein Biogenesis |
Zdroj: | eLife. 11 |
ISSN: | 2050-084X |
Popis: | Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in Plasmodium falciparum malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast. PPS knockdown is lethal to parasites, rescued by IPP and long- (C50) but not short-chain (≤C20) prenyl alcohols, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting. |
Databáze: | OpenAIRE |
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