Critical role for isoprenoids in apicoplast biogenesis by malaria parasites

Megan Okada, Krithika Rajaram, Russell P. Swift, Amanda Mixon, John Alan Maschek, Sean T. Prigge, Paul A. Sigala

Research output: Contribution to journalArticlepeer-review


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 unchar-acterized 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 prenyla-tion 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 utiliza-tion in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.

Original languageEnglish (US)
Article numbere73208
StatePublished - Mar 2022

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Neuroscience


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