Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites

Author:

Crispim Marcell,Verdaguer Ignasi Bofill,Hernández Agustín,Kronenberger Thales,Fenollar Àngel,Yamaguchi Lydia Fumiko,Alberione María Pía,Ramirez Miriam,de Oliveira Sandra Souza,Katzin Alejandro MiguelORCID,Izquierdo LuisORCID

Abstract

A proposed treatment for malaria is a combination of fosmidomycin and clindamycin. Both compounds inhibit the methylerythritol 4-phosphate (MEP) pathway, the parasitic source of farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively). Both FPP and GGPP are crucial for the biosynthesis of several essential metabolites such as ubiquinone and dolichol, as well as for protein prenylation. Dietary prenols, such as farnesol (FOH) and geranylgeraniol (GGOH), can rescue parasites from MEP inhibitors, suggesting the existence of a missing pathway for prenol salvage via phosphorylation. In this study, we identified a gene in the genome of P. falciparum, encoding a transmembrane prenol kinase (PolK) involved in the salvage of FOH and GGOH. The enzyme was expressed in Saccharomyces cerevisiae, and its FOH/GGOH kinase activities were experimentally validated. Furthermore, conditional knockout parasites (Δ-PolK) were created to investigate the biological importance of the FOH/GGOH salvage pathway. Δ-PolK parasites were viable but displayed increased susceptibility to fosmidomycin. Their sensitivity to MEP inhibitors could not be rescued by adding prenols. Additionally, Δ-PolK parasites lost their capability to utilize prenols for protein prenylation. Experiments using culture medium supplemented with whole/delipidated human plasma in transgenic parasites revealed that human plasma has components that can diminish the effectiveness of fosmidomycin. Mass spectrometry tests indicated that both bovine supplements used in culture and human plasma contain GGOH. These findings suggest that the FOH/GGOH salvage pathway might offer an alternate source of isoprenoids for malaria parasites when de novo biosynthesis is inhibited. This study also identifies a novel kind of enzyme related to isoprenoid metabolism.

Funder

Fundação de Amparo à Pesquisa do Estado de São Paulo

Spanish Ministry of Science & Innovation

Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires

FPU Fellowship from the Spanish Ministry of Universities

Federal Ministry of Education and Research

the Baden-Württemberg Ministry of Science

Publisher

Public Library of Science (PLoS)

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Absence of farnesol salvage in Candida albicans and probably in other fungi;Applied and Environmental Microbiology;2024-07-24

2. Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites;Advances in Pharmacological and Pharmaceutical Sciences;2024-05-10

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