Posttranslational Modification of Human Glyoxalase 1 Indicates Redox-Dependent Regulation 英文参考文献.docVIP

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Posttranslational Modification of Human Glyoxalase 1 Indicates Redox-Dependent Regulation 英文参考文献.doc

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Posttranslational Modification of Human Glyoxalase 1 Indicates Redox-Dependent Regulation 英文参考文献

PosttranslationalModificationofHumanGlyoxalase1 IndicatesRedox-DependentRegulation GerdBirkenmeier1,ChristinStegemann2,RalfHoffmann2,RobertGu¨nther3,KlausHuse4 ,Claudia Birkemeyer5* 1FacultyofMedicine,InstituteofBiochemistry,UniversityofLeipzig,Leipzig,Germany,2FacultyofChemistryandMineralogy,CenterforBiotechnologyandBiomedicine, InstituteofBioanalyticalChemistry,UniversityofLeipzig,Leipzig,Germany,3FacultyofBiosciences,PharmacyandPsychology,InstituteofBiochemistry,Universityof Leipzig,Leipzig,Germany,4LeibnizInstituteforAgeResearch–FritzLipmannInstitutee.V.,Jena,Germany,5FacultyofChemistryandMineralogy,InstituteofAnalytical Chemistry,UniversityofLeipzig,Leipzig,Germany Abstract Background: Glyoxalase1 (Glo1)andglyoxalase 2(Glo2) areubiquitouslyexpressed cytosolic enzymesthat catalyze the conversionoftoxica-oxo-aldehydesintothecorrespondinga-hydroxyacidsusingL-glutathione(GSH)asacofactor.Human Glo1existsinvariousisoforms;however,thenatureofitsmodificationsandtheirdistinctfunctionalassignmentismostly unknown. Methodology/PrincipalFindings:WecharacterizednativeGlo1purifiedfromhumanerythrocytesbymassspectrometry. The enzymewasfoundtoundergo four sofar unidentified posttranslational modifications: (i) removalofthe N-terminal methionine1,(ii)N-terminalacetylationatalanine2,(iii)avicinaldisulfidebridgebetweencysteineresidues19and20,and (iv) a mixed disulfide with glutathione on cysteine 139. Glutathionylation of Glo1 was confirmed by immunological methods. Both, N-acetylation and the oxidation state of Cys19/20, did not impact enzyme activity. In contrast, glutathionylation strongly inhibited Glo1 activity in vitro. The discussed mechanism for enzyme inhibition by glutathionylationwasvalidatedbymoleculardynamicssimulation. Conclusion/Significance: It is shown for the first time that Glo1 activity directly can be regulated by an oxidative posttranslationalmodificationthatwasfoundinthenativeenzyme,i.e.,glutathionylation.InhibitionofGlo1bychemical reaction with its c