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De novo biosynthesis of sterols and fatty acids in the Trypanosoma brucei procyclic form: Carbon source preferences and metabolic flux redistributions

dc.rights.licenseopenen_US
atmire.cua.enabled
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorMILLERIOUX, Yoann
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorMAZET, Muriel
hal.structure.identifierLaboratoire de biogenèse membranaire [LBM]
dc.contributor.authorBOUYSSOU, Guillaume
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorALLMANN, Stefan
dc.contributor.authorKIEMA, Tiila-Riikka
dc.contributor.authorBERTIAUX, Eloise
hal.structure.identifierLaboratoire de biogenèse membranaire [LBM]
dc.contributor.authorFOUILLEN, Laetitia
dc.contributor.authorTHAPA, Chandan
hal.structure.identifierCentre de résonance magnétique des systèmes biologiques [CRMSB]
dc.contributor.authorBIRAN, Marc
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorPLAZOLLES, Nicolas
hal.structure.identifierLaboratoire de biogenèse membranaire [LBM]
dc.contributor.authorDITTRICH-DOMERGUE, Franziska
dc.contributor.authorCROUZOLS, Aline
dc.contributor.authorWIERENGA, Rik
dc.contributor.authorROTUREAU, Brice
hal.structure.identifierLaboratoire de biogenèse membranaire [LBM]
dc.contributor.authorMOREAU, Patrick
IDREF: 058610723
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorBRINGAUD, Frédéric
dc.date.accessioned2023-06-22T15:20:26Z
dc.date.available2023-06-22T15:20:26Z
dc.date.issued2018-05-29
dc.identifier.issn1553-7366en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/182775
dc.description.abstractEnDe novo biosynthesis of lipids is essential for Trypanosoma brucei, a protist responsible for the sleeping sickness. Here, we demonstrate that the ketogenic carbon sources, threonine, acetate and glucose, are precursors for both fatty acid and sterol synthesis, while leucine only contributes to sterol production in the tsetse fly midgut stage of the parasite. Degradation of these carbon sources into lipids was investigated using a combination of reverse genetics and analysis of radio-labelled precursors incorporation into lipids. For instance, (i) deletion of the gene encoding isovaleryl-CoA dehydrogenase, involved in the leucine degradation pathway, abolished leucine incorporation into sterols, and (ii) RNAi-mediated down-regulation of the SCP2-thiolase gene expression abolished incorporation of the three ketogenic carbon sources into sterols. The SCP2-thiolase is part of a unidirectional two-step bridge between the fatty acid precursor, acetyl-CoA, and the precursor of the mevalonate pathway leading to sterol biosynthesis, 3-hydroxy-3-methylglutaryl-CoA. Metabolic flux through this bridge is increased either in the isovaleryl-CoA dehydrogenase null mutant or when the degradation of the ketogenic carbon sources is affected. We also observed a preference for fatty acids synthesis from ketogenic carbon sources, since blocking acetyl-CoA production from both glucose and threonine abolished acetate incorporation into sterols, while incorporation of acetate into fatty acids was increased. Interestingly, the growth of the isovaleryl-CoA dehydrogenase null mutant, but not that of the parental cells, is interrupted in the absence of ketogenic carbon sources, including lipids, which demonstrates the essential role of the mevalonate pathway. We concluded that procyclic trypanosomes have a strong preference for fatty acid versus sterol biosynthesis from ketogenic carbon sources, and as a consequence, that leucine is likely to be the main source, if not the only one, used by trypanosomes in the infected insect vector digestive tract to feed the mevalonate pathway.
dc.description.sponsorshipMetabolisme de l'acetyl-CoA et de l'acetate chez les trypanosomes: identification de nouvelles voies métaboliques spécifiques aux parasitesen_US
dc.description.sponsorshipAlliance française contre les maladies parasitaires - ANR-11-LABX-0024en_US
dc.description.sponsorshipInfrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences
dc.description.sponsorshipVoies métaboliques glycosomales non glycolytiques: nouvelles fonctions pour le développement et la virulence des trypanosomes
dc.language.isoENen_US
dc.rights.urihttp://creativecommons.org/licenses/by/
dc.subjectcell-cycle
dc.subjectlipbiosyntesis
dc.subject.enacetyl-coa
dc.subject.endependent enzyme
dc.subject.enenergy-metabolism
dc.subject.enproline metabolism
dc.subject.enmolecular characterization
dc.subject.enleishmania-mexicana
dc.subject.enblood-sream forms
dc.subject.ensuccinate coa-transferase
dc.subject.meshAcetates
dc.subject.meshAcetyl Coenzyme A
dc.subject.meshGene Knockout Techniques
dc.subject.meshGlucose
dc.subject.meshInsect Vectors
dc.subject.meshLeucine
dc.subject.meshMevalonic Acid
dc.subject.meshProline
dc.subject.meshSterols
dc.subject.meshThreonine
dc.subject.meshTrypanosoma brucei brucei
dc.subject.meshTsetse Flies
dc.subject.meshAcetyltransferases
dc.subject.meshAcyl Coenzyme A
dc.subject.meshAlcohol Oxidoreductases
dc.subject.meshAnimals
dc.subject.meshCarbon
dc.subject.meshFatty Acids
dc.subject.meshGene Expression Regulation
dc.title.enDe novo biosynthesis of sterols and fatty acids in the Trypanosoma brucei procyclic form: Carbon source preferences and metabolic flux redistributions
dc.typeArticle de revueen_US
dc.identifier.doi10.1371/journal.ppat.1007116en_US
dc.subject.halSciences du Vivant [q-bio]en_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologieen_US
dc.subject.halSciences du Vivant [q-bio]/Microbiologie et Parasitologie/Parasitologieen_US
dc.description.sponsorshipEuropeA systematic analysis of parasite metabolism - from metabolism to interventionen_US
bordeaux.journalPLoS Pathogensen_US
bordeaux.pagee1007116en_US
bordeaux.volume14en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.issue5en_US
bordeaux.institutionCNRSen_US
bordeaux.institutionUniversité de Bordeaux
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierpasteur-01849809
hal.version1
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
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