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Vitamin B6 biosynthesis by the malaria parasite Plasmodium falciparum: biochemical and structural insights

Gengenbacher, Martin
Raschle, Thomas
Flicker, Karlheinz
Sinning, Irmgard
Müller, Sylke
Macheroux, Peter
Tews, Ivo
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Published in Journal of Biological Chemistry. 2006, vol. 281, no. 6, p. 3633-3641
Abstract Vitamin B6 is one of nature's most versatile cofactors. Most organisms synthesize vitamin B6 via a recently discovered pathway employing the proteins Pdx1 and Pdx2. Here we present an in-depth characterization of the respective orthologs from the malaria parasite, Plasmodium falciparum. Expression profiling of Pdx1 and -2 shows that blood-stage parasites indeed possess a functional vitamin B6 de novo biosynthesis. Recombinant Pdx1 and Pdx2 form a complex that functions as a glutamine amidotransferase with Pdx2 as the glutaminase and Pdx1 as pyridoxal-5 '-phosphate synthase domain. Complex formation is required for catalytic activity of either domain. Pdx1 forms a chimeric bi-enzyme with the bacterial YaaE, a Pdx2 ortholog, both in vivo and in vitro, although this chimera does not attain full catalytic activity, emphasizing that species-specific structural features govern the interaction between the protein partners of the PLP synthase complexes in different organisms. To gain insight into the activation mechanism of the parasite bi-enzyme complex, the three-dimensional structure of Pdx2 was determined at 1.62 A. The obstruction of the oxyanion hole indicates that Pdx2 is in a resting state and that activation occurs upon Pdx1-Pdx2 complex formation.
Keywords AnimalsAntigensProtozoan/chemistryBacillus subtilis/metabolismBlottingWesternCatalysisCatalytic DomainCloningMolecularCrystallographyX-RayDatabases as TopicElectrophoresisPolyacrylamide GelGenetic Complementation TestGlutaminase/chemistry/metabolismImmunoblottingIonsMalaria/parasitologyModelsMolecularMolecular Sequence DataOligonucleotides/chemistryPlasmodium falciparum/metabolismProtein BindingProtein ConformationProtein StructureTertiaryProtozoan Proteins/chemistryRecombinant Proteins/chemistryTime FactorsVitamin B 6/biosynthesis/chemistry
PMID: 16339145
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GENGENBACHER, Martin et al. Vitamin B6 biosynthesis by the malaria parasite Plasmodium falciparum: biochemical and structural insights. In: Journal of Biological Chemistry, 2006, vol. 281, n° 6, p. 3633-3641.

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Deposited on : 2016-11-29

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