A Δ38 Deletion Variant of Human Transketolase as a Model of Transketolase-Like Protein 1 Exhibits No Enzymatic Activity 英文参考文献.docVIP

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A Δ38 Deletion Variant of Human Transketolase as a Model of Transketolase-Like Protein 1 Exhibits No Enzymatic Activity 英文参考文献.doc

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A Δ38 Deletion Variant of Human Transketolase as a Model of Transketolase-Like Protein 1 Exhibits No Enzymatic Activity 英文参考文献

AD38DeletionVariantofHumanTransketolaseasa ModelofTransketolase-LikeProtein1ExhibitsNo EnzymaticActivity StefanSchneider,StefanLu¨dtke,KathrinSchro¨der-Tittmann,CindyWechsler,DaniloMeyer, KaiTittmann* Albrecht-von-Haller-InstituteandGo¨ttingenCenterforMolecularBiosciences,DepartmentofBioanalytics,Georg-August-UniversityGo¨ttingen,Germany Abstract Besidestransketolase(TKT),athiamin-dependentenzymeofthepentosephosphatepathway,thehumangenomeencodes fortwocloselyrelatedtransketolase-likeproteins,whichshareahighsequenceidentitywithTKT.Transketolase-likeprotein 1 (TKTL1) has beenimplicated in cancerogenesis as its cellular expression levelswerereported to directly correlate with invasionefficiencyofcancercellsandpatientmortality.IthasbeenproposedthatTKTL1exertsitsfunctionbycatalyzingan unusual enzymatic reaction, a hypothesis that has been the subject of recent controversy. The most striking difference between TKTL1 and TKT is a deletion of 38 consecutive amino acids in the N-terminal domain of the former, which constitutepartoftheactivesiteinauthenticTKT.OurstructuralandsequenceanalysissuggestedthatTKTL1mightnot possesstransketolaseactivity.InordertotestthishypothesisintheabsenceofarecombinantexpressionsystemforTKTL1 and resilient data on its biochemical properties, we have engineered and biochemically characterized a ‘‘pseudo-TKTL1’’ D38deletionvariantofhumanTKT(TKTD38)asaviablemodelofTKTL1.Althoughtheisolatedproteinisproperlyfolded underinvitroconditions,boththermalstabilityaswellasstabilityoftheTKT-specifichomodimericassemblyaremarkedly reduced. Circular dichroism and NMR spectroscopic analysis further indicates that TKTD38 is unable to bind the thiamin cofactor in a specific manner, even at superphysiological concentrations. No transketolase activity of TKTD38 can be detectedforconversionofphysiologicalsugarsubstratesthusarguingagainstanintrinsicallyencodedenzymaticfunction ofTKTL1intumorcellmetabolism. Citation: Schneider S, Lu¨dtke S, Schro¨der-Tittmann K, Wechsl