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Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites.
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 Miguel; Izquierdo, Luis.
Afiliación
  • Crispim M; Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil.
  • Verdaguer IB; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
  • Hernández A; Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil.
  • Kronenberger T; Center for Biological and Health Sciences, Integrated Unit for Research in Biodiversity (BIOTROP-CCBS), Federal University of São Carlos, São Carlos, Brazil.
  • Fenollar À; Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tuebingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Tübingen, Germany.
  • Yamaguchi LF; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
  • Alberione MP; Excellence Cluster "Controlling Microbes to Fight Infections" (CMFI), Tübingen, Germany.
  • Ramirez M; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
  • de Oliveira SS; Institute for Technological Research of São Paulo State, Nutabes, São Paulo, Brazil.
  • Katzin AM; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
  • Izquierdo L; Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain.
PLoS Pathog ; 20(1): e1011557, 2024 Jan.
Article en En | MEDLINE | ID: mdl-38277417
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.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Parásitos / Hemiterpenos / Diterpenos / Pentanoles / Fosfomicina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Brasil

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Parásitos / Hemiterpenos / Diterpenos / Pentanoles / Fosfomicina Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: PLoS Pathog Año: 2024 Tipo del documento: Article País de afiliación: Brasil