دورية أكاديمية
Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites.
| العنوان: | Beyond the MEP Pathway: A novel kinase required for prenol utilization by malaria parasites. |
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| المؤلفون: | Marcell Crispim, Ignasi Bofill Verdaguer, Agustín Hernández, Thales Kronenberger, Àngel Fenollar, Lydia Fumiko Yamaguchi, María Pía Alberione, Miriam Ramirez, Sandra Souza de Oliveira, Alejandro Miguel Katzin, Luis Izquierdo |
| المصدر: | PLoS Pathogens, Vol 20, Iss 1, p e1011557 (2024) |
| بيانات النشر: | Public Library of Science (PLoS), 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Immunologic diseases. Allergy LCC:Biology (General) |
| مصطلحات موضوعية: | Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1553-7366 1553-7374 |
| Relation: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011557&type=printable; https://doaj.org/toc/1553-7366; https://doaj.org/toc/1553-7374 |
| DOI: | 10.1371/journal.ppat.1011557&type=printable |
| DOI: | 10.1371/journal.ppat.1011557 |
| URL الوصول: | https://doaj.org/article/237ca26c1906426da1acea6b60a8f15a |
| رقم الأكسشن: | edsdoj.237ca26c1906426da1acea6b60a8f15a |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 15537366 15537374 |
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| DOI: | 10.1371/journal.ppat.1011557&type=printable |