Critical role for isoprenoids in apicoplast biogenesis by malaria parasites

eLife

Amanda Mixon¹  Paul A Sigala¹  Megan Okada¹  Sean T Prigge²  Russell P Swift²  Krithika Rajaram²  John Alan Maschek³ 

[1] Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States;Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, United States;Metabolomics Core, University of Utah Health Sciences Center, Salt Lake City, United States;

关键词: malaria;    isoprenoids;    apicoplast;    organelle biogenesis;    polyprenol synthase;   

DOI  :  10.7554/eLife.73208

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown