Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation 英文参考文献.docVIP

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Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation 英文参考文献.doc

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Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation 英文参考文献

EffectsofSingleNucleotidePolymorphismsonHuman N-Acetyltransferase2StructureandDynamicsby MolecularDynamicsSimulation M.Rajasekaran1,2,3,SanthanamAbirami3,4,5,ChinpanChen1* 1InstituteofBiomedicalSciences,AcademiaSinica,Nankang,Taipei,Taiwan,RepublicofChina,2DepartmentofLifeScience,NationalTsingHuaUniversity,Hsinchu, Taiwan, Republic of China, 3Chemical Biology and Molecular Biophysics, Institute of Biological Chemistry, Taiwan International Graduate Program, Academia Sinica, Nankang,Taipei,Taiwan,RepublicofChina,4InstituteofBiologicalChemistry,AcademiaSinica,Nankang,Taipei,Taiwan,RepublicofChina,5InstituteofBiochemical Sciences,CollegeofLifeSciences,NationalTaiwanUniversity,Taipei,Taiwan,RepublicofChina Abstract Background: Arylamine N-acetyltransferase 2(NAT2) is an important catalytic enzymethat metabolizes thecarcinogenic arylamines, hydrazine drugs and chemicals. This enzyme is highly polymorphic in different human populations. Several polymorphisms of NAT2, including the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E,areclassifiedasslowacetylators,whereasthewild-typeNAT2isclassifiedasafastacetylator.Theslowacetylators are often associated with drug toxicity and efficacy as well as cancer susceptibility. The biological functions of these 7 mutationshavepreviouslybeencharacterized,butthestructuralbasisbehindthereducedcatalyticactivityandreduced proteinlevelisnotclear. Methodology/PrincipalFindings:WeperformedmultiplemoleculardynamicssimulationsofthesemutantsaswellasNAT2 toinvestigatethestructuralanddynamicaleffectsthroughouttheproteinstructure,specificallythecatalytictriad,cofactor binding site, and the substrate binding pocket. None of these mutations induced unfolding; instead, their effects were confinedtotheinter-domain,domain3and17-residueinsertregion,wheretheflexibilitywassignificantlyreducedrelative to the wild-type. Structural effects of these mutations propagate through space and cause a change in catalytic triad conf