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1、PROTEINS:Structure,Function,andBioinformatics57:758–771(2004)MolecularRecognitionofAldehydesbyAldehydeDehydrogenaseandMechanismofNucleophileActivationTroyWymore,1*JohnHempel,2SamuelS.Cho,3AlexanderD.MacKerell,Jr.,3HughB.Nicholas,Jr.,1and1DavidW.DeerfieldII1PittsburghSupercomputingCenter,Biomedi
2、calInitiativeGroup,Pittsburgh,Pennsylvania2DepartmentofBiologicalSciences,UniversityofPittsburgh,Pittsburgh,Pennsylvania3UniversityofMaryland,SchoolofPharmacy,Baltimore,MarylandABSTRACTExperimentalstructuraldataonshowntodetoxifyametaboliteofthecancerchemothera-thestateofsubstratesboundtoclass3
3、Aldehydepeuticagentcyclophosphoamide(CP),leadingtodrugDehydrogenases(ALDH3A1)iscurrentlyunknown.2resistance.Therefore,inhibitorsofALDH3takenwithCPWehaveutilizedmolecularmechanics(MM)simula-drugsmayleadtomoreeffectivetreatmentsforthosetions,inconjunctionwithnewforcefieldparame-experiencingdrugre
4、sistancetoCP.Designinginhibitorstersforaldehydes,tostudytheatomicdetailsofofALDH3shouldbebasedonathoroughknowledgeofthebenzaldehydebindingtoALDH3A1.Ourresultsindi-reactionmechanism.SeveralinsightsintotheALDHcatethatwhilethenucleophilicCys243mustbeinmechanismofconvertingbenzaldehydetobenzoicaci
5、dtheneutralstatetoformwhatarecommonlycalledhavebeenprovidedbythecrystalstructure,3site-directednear-attackconformers(NACs),thesestructuresdomutagenesis,4–6andNMR.7ThesestudiesprovidethenotcorrelatewithincreasedcomplexationenergybasisbywhichtocarryoutadvancedmolecularmodelingcalculatedwiththeMM
6、-GeneralizedBornMolecu-studiesontheenzyme.larVolume(GBMV)method.ThenegativelychargedALDH3isahomodimericenzyme;eachsubunitcontainsCys243(thiolateform)ofALDH3A1alsobindsbenz-anicotinamideadeninedinucleotide(NAD)-bindingdo-aldehydeinastableconformationbutinthiscom-3main,acatalyticdomain,andanolig
7、omerizationdomain.plexthesulfurofCys243isorientedawayfromA15-Å-longfunnel-shapedpassageformedbetweenthesebenzaldehydeyetyieldsthemostfavorableMM-domainsleadstotheactivesite.NADbindstothefaceofGBMVcomplexationenergy.Theidentityofthethedi
