The methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum

dc.creatorCassera, MB
dc.creatorGozzo, FC
dc.creatorD'Alexandri, FL
dc.creatorMerino, EF
dc.creatordel Portillo, HA
dc.creatorPeres, VJ
dc.creatorAlmeida, IC
dc.creatorEberlin, MN
dc.creatorWunderlich, G
dc.creatorWiesner, J
dc.creatorJomaa, H
dc.creatorKimura, EA
dc.creatorKatzin, AM
dc.date2004
dc.dateDEC 10
dc.date2014-11-14T17:09:09Z
dc.date2015-11-26T17:15:55Z
dc.date2014-11-14T17:09:09Z
dc.date2015-11-26T17:15:55Z
dc.date.accessioned2018-03-29T00:04:09Z
dc.date.available2018-03-29T00:04:09Z
dc.identifierJournal Of Biological Chemistry. Amer Soc Biochemistry Molecular Biology Inc, v. 279, n. 50, n. 51749, n. 51759, 2004.
dc.identifier0021-9258
dc.identifierWOS:000225493400007
dc.identifier10.1074/jbc.M408360200
dc.identifierhttp://www.repositorio.unicamp.br/jspui/handle/REPOSIP/73636
dc.identifierhttp://www.repositorio.unicamp.br/handle/REPOSIP/73636
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/73636
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1282165
dc.descriptionTwo genes encoding the enzymes 1-deoxy-D-xylulose-5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase have been recently identified, suggesting that isoprenoid biosynthesis in Plasmodium falciparum depends on the methylerythritol phosphate ( MEP) pathway, and that fosmidomycin could inhibit the activity of 1-deoxy-D-xylulose-5-phosphate reductoisomerase. The metabolite 1-deoxy-D-xylulose-5-phosphate is not only an intermediate of the MEP pathway for the biosynthesis of isopentenyl diphosphate but is also involved in the biosynthesis of thiamin (vitamin B-1) and pyridoxal (vitamin B-6) in plants and many microorganisms. Herein we report the first isolation and characterization of most downstream intermediates of the MEP pathway in the three intraerythrocytic stages of P. falciparum. These include, 1-deoxy-D-xylulose-5-phosphate, 2-C-methyl-D-erythritol-4-phosphate, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol, 4-(cytidine-5-diphospho)-2-C-methyl-D-erythritol-2-phosphate, and 2-C-methyl-D-erythritol-2,4-cyclodiphosphate. These intermediates were purified by HPLC and structurally characterized via biochemical and electrospray mass spectrometric analyses. We have also investigated the effect of fosmidomycin on the biosynthesis of each intermediate of this pathway and isoprenoid biosynthesis (dolichols and ubiquinones). For the first time, therefore, it is demonstrated that the MEP pathway is functionally active in all intraerythrocytic forms of P. falciparum, and de novo biosynthesis of pyridoxal in a protozoan is reported. Its absence in the human host makes both pathways very attractive as potential new targets for antimalarial drug development.
dc.description279
dc.description50
dc.description51749
dc.description51759
dc.languageen
dc.publisherAmer Soc Biochemistry Molecular Biology Inc
dc.publisherBethesda
dc.publisherEUA
dc.relationJournal Of Biological Chemistry
dc.relationJ. Biol. Chem.
dc.rightsfechado
dc.sourceWeb of Science
dc.subject1-deoxy-d-xylulose 5-phosphate Reductoisomerase
dc.subjectMevalonate-independent Pathway
dc.subjectPerformance Liquid-chromatography
dc.subjectEscherichia-coli K-12
dc.subjectIsoprenoid Biosynthesis
dc.subjectIsopentenyl Diphosphate
dc.subjectNonmevalonate Pathway
dc.subjectHigher-plants
dc.subject2c-methyl-d-erythritol 2,4-cyclodiphosphate
dc.subjectHeterologous Expression
dc.titleThe methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum
dc.typeArtículos de revistas


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