Affiliation:
1. Department of Biochemistry, University of Utah School of Medicine
2. Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health
3. Metabolomics Core, University of Utah Health Sciences Center
Abstract
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.
Funder
National Institute of General Medical Sciences
Congressionally Directed Medical Research Programs
National Institute of Allergy and Infectious Diseases
Burroughs Wellcome Fund
Pew Charitable Trusts
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bloomberg Philanthropies
Johns Hopkins Malaria Research Institute
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
15 articles.
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