Critical Role for Isoprenoids in Apicoplast Biogenesis by Malaria Parasites

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 lumen. PPS knockdown is lethal to parasites, rescued by IPP, 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.

Disrupting the plastidic iron-sulfur cluster biogenesis pathway in Toxoplasma gondii has pleiotropic effects irreversibly impacting parasite viability

“…This confirms the importance of the apicoplast Fe-S cluster synthesis machinery for isoprenoid metabolism. In Plasmodium , interfering with apicoplast-hosted isoprenoid production affects the morphology of the organelle ( 76 ), but depletion of IspG and IspH does not lead to loss of the apicoplast ( 40 ), while interfering with the SUF pathway does ( 15 ). We also observe a late impact on the organelle ( Fig.…”

Disrupting the plastid-hosted iron-sulfur cluster biogenesis pathway in Toxoplasma gondii has pleiotropic effects irreversibly impacting parasite viability

“…This confirms the importance of the apicoplast Fe-S cluster synthesis machinery for isoprenoid metabolism. In Plasmodium, interfering with apicoplast-hosted isoprenoid production affects the morphology of the organelle (71) but depletion of IspG and IspH does not lead to loss of the apicoplast (37), while interfering with the SUF pathway does (13). We also observe a late impact on the organelle (Fig.…”