外文翻译-- Relationships between Inhibition Constants, Types of.PDF外文翻译-- Relationships between Inhibition Constants, Types of.PDF

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RELATIONSHIPSBETWEENINHIBITIONCONSTANTS,TYPESOFINHIBITIONANDIC50CALCULATIONANDCOMPARISONONIC50OFTWOMODELTYROSINASEINHIBITORSHAIRONGMAO1,JIANGANGXIE1,QIMENGZHANG2,XINYUL3,SHUBAILI2,1DEPARTMENTOFCHEMISTRY,ZHENGZHOUTEACHERSCOLLEGE,ZHENGZHOU,CHINA2DEPARTMENTOFCHEMICALENGINEERINGTECHNOLOGY,CHANGZHOUINSTITUTEOFENGINEERINGTECHNOLOGY,CHANGZHOU,CHINA3INSTITUTEOFFINECHEMICALS,JIANGSUPOLYTECHNICUNIVERSITY,CHANGZHOU,CHINACORRESPONDINGAUTHOREMAILSBLIEMAILCZIENETABSTRACTCALCULATINGMETHODSFORINHIBITORCONCENTRATIONIC50LEADINGTO50ACTIVITYLOSTFORDIPHENOLASEACTIVITYOFANOVELPARABOLICCOMPETITIVEINHIBITORTHETRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLE,TFTAANDANOVELMIXEDINHIBITORE41IMIDAZOYLMETHYLCINNAMICACIDOZAGRELWEREDERIVEDONTHEBASISOFKINETICSOFTYROSINASEINHIBITIONTHESEMETHODSWEREAPPLIEDTOCALCULATEIC50VALUESOFTHETWOTYROSINASEINHIBITINGCOMPOUNDSTHEEXPERIMENTALIC50VALUESOFTFTAANDOZAGRELWERE419ΜMAND345MM,RESPECTIVIELYMOREOVER,THECALCULATEDIC50VALUEOFTFTAANDOZAGRELWERE828ΜMAND315MM,RESPECTIVELYTHECALCULATIONRESULTOFOZAGRELISCLOSERTOEXPERIMENTALDATAKEYWORDSTYROSINASE;IC50;TRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLETFTA;E41IMIDAZOYLMETHYLCINNAMICACIDOZAGRELIINTRODUCTIONTHEREGULATIONOFENZYMEACTIVITYISOFGREATINTERESTFORBIOCHEMICALRESEARCHPURPOSESANDFORANUMBEROFAPPLICATIONSINMEDICINE,PHYSIOLOGY,ANDPHARMACOLOGYINHIBITIONOFENZYMESFROMANYBIOLOGICALSOURCECANBEACHIEVEDBYSEVERALAGENTS,SUCHASSELFINACTIVATINGSUBSTRATESANDREVERSIBLEORIRREVERSIBLEINHIBITORSTYROSINASEEC114181ISACOPPERCONTAININGENZYMEWITHRESPONSIBILITIESFORSKIN,HAIR,MELANIZATIONANDENZYMATICBROWNINGINFRUITSANDVEGETABLES13ITCATALYZESTHEHYDROXYLATIONOFMONOPHENOLSMONOPHENOLASEACTIVITYANDTHEOXIDATIONOFODIPHENOLSTOOQUINONESDIPHENOLASEACTIVITY,BOTHDEPENDINGONMOLECULAROXYGEN4,5THEBROWNINGISRESPONSIBLEFORLOSSINNUTRITIONALQUALITY,ANDTHEREFOREBECOMESAMAJORPROBLEMINTHEFOODINDUSTRYTHEREFORE,THECONTROLOFTHETYROSINASEACTIVITYISOFIMPORTANCEINPREVENTINGTHESYNTHESISOFMELANININTHEBROWNINGOFMUSHROOMSANDOTHERVEGETABLESANDFRUITSMANYEFFORTSHAVEBEENPUTINTHESEARCHFORFEASIBLEANDEFFECTIVETYROSINASEINHIBITORS69INOURSEARCHFORTYROSINASENOVELINHIBITORS,TRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLES10,ANDOZAGRELANALOGUES11,WEREFOUNDTOHAVEOBVIOUSINHIBITORYEFFECTSONTHEMONOPHENOLASEACTIVITYANDTHEDIPHENOLASEACTIVITYOFMUSHROOMTYROSINASETHEIC50INHIBITORCONCENTRATIONLEADINGTO50ACTIVITYLOSTISAMEASUREOFTHEEFFECTIVENESSOFACOMPOUNDININHIBITINGBIOLOGICALORBIOCHEMICALFUNCTIONOFTEN,THECOMPOUNDINQUESTIONISADRUGCANDIDATETHISQUANTITATIVEMEASUREINDICATESHOWMUCHOFAPARTICULARDRUGOROTHERINHIBITORSNEEDEDTOINHIBITAGIVENBIOLOGICALPROCESSBYHALFITISCOMMONLYUSEDASAMEASUREOFANTAGONISTDRUGPOTENCYINPHARMACOLOGICALRESEARCHHOWEVER,ITAPPEARSNOTTOHAVEBEENNOTICEDPREVIOUSLYTHATTHEREISAVERYSIMPLERELATIONSHIPBETWEENIC50WITHINHIBITIONCONSTANTSANDTYPESOFINHIBITIONTYPETHEREFORE,THEAIMOFTHEPRESENTWORKWASTODEVELOPAMETHODTOCALCULATEIC50OFTWONOVELTYROSINASEINHIBITORSIICALCULATIONANDCOMPARISONONIC50ACALCULATIONOFIC50FORTHEPARABOLICCOMPETITIVEINHIBITORTHETRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLESEXHIBITANTIMICROBIAL,ANTIVIRALANDANTITUMORACTIVITIESANDHAVEARANGEOFIMPORTANTAPPLICATIONSINPHARMACEUTICALANDAGROCHEMICALINDUSTRIES12NNNF3COHFIG1STRUCTUREOFTHETRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLETFTAWEFOUNDANOVELTRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLETFTA,SEESTRUCTUREINFIG1CANINHIBITMUSHROOMTYROSINASEACTIVITYIC50419ΜMWITHITSINCREASINGCONCENTRATIONSTHEINHIBITIONKINETICS,ANALYZEDBYLINEWEAVERBURKPLOTS,INDICATEDTFTATOBEAPARABOLICCOMPETITIVEINHIBITOROFDIPHENOLASEWHENLDOPAWASUSEDASSUBSTRATEITISSUGGESTEDTHATTWOTFTAMOLECULESCANCOMBINEWITHFREETYROSINASETOFORMADEADENDCOMPLEXATENZYMEACTIVESITETHEINHIBITIONCONSTANTSKI1FORINHIBITORENZYMECOMPLEXANDKI2FORINHIBITORENZYMEINHIBITOR9781424447138/10/25002010IEEECOMPLEXWEREESTIMATEDTOBE929MMAND136MM,RESPECTIVELYTHEMECHANISMREPRESENTINGPARABOLICCOMPETITIVEINHIBITIONFORTHETYROSINASECATALYZEDREACTIONISASFOLLOWSESESEPK1K2K1K3K3K4IIEIK4EI2IIE,S,I,PDENOTEENZYMEMUSHROOMTYROSINASE,SUBSTRATELDOPA,INHIBITORTFTA,ANDPRODUCTDOPACHROME,RESPECTIVELY;ES,EI,ANDEI2ARETHERESPECTIVECOMPOUNDSASITISUSUALLYTHECASETHATSETANDIETINTHESTEADYSTATE,THERATEOFFORMATIONANDDISAPPEARANCEOFTHECOMPLEXESAREIDENTICALESES211KKK−1133IEEIKK−12EIIEI244−KK13THEEXPRESSIONSFORTHETOTALENZYMECONCENTRATIONANDTHEREACTIONRATEEIEIESEE2T14ES2KV15INSERTIONOFTHEEXPRESSIONSFORE,EI,ANDEI2INTERMOFES,INTOTHEEXPRESSIONFORTHETOTALENZYMECONCENTRATIONGIVESESI1IS1SE4433121121T⎥⎦⎤⎢⎣⎡⋅−−−−KKKKKKKKKK16I1ISSE4433121121T2−−−−⋅KKKKKKKKKKKV17BECAUSEK1K2/K1ISTHEMICHAELISCONSTANTKMFORTHEREACTIONINTHEABSENCEOFINHIBITOR,K3/K3ISTHEEQUILIBRIUMCONSTANTKI1FORTHEDISSOCIATIONOFTHECOMPLEXEIINTOEANDI,ANDK4/K4ISTHEEQUILIBRIUMCONSTANTKI2FORTHEDISSOCIATIONOFTHECOMPLEXEI2INTOEIANDI,THERATEEQUATIONMAYBEWRITTENINTHEFORMII1SSI2I12I1MMAXKKKKVV18WHICHINRECIPROCALFORBECOMESMAXI2I12I1MAXM1II1S1VKKKVKV⋅19ITISEVIDENTFROMEQ19THATTHESLOPEOFLINEWEAVERBURKLINESISINFLUENCEDBYTHECHANGINGIANDI2ACCORDINGTOEQ18,INTHEABSENCEOFTFTZ,THEKINETICFUNCTIONISSSMMAX0KVV110THEINHIBITIONRATIO01100VIV−SSII1SS1MMAXI2I12I1MMAX−KVKKKKV111WHENIREACHES50,IIC50,SO,II1SS21I2I12I1MMKKKKK112THEIC50VALUETHENEGATIVEVALUESHOULDBEREMOVEDISMM2MMI1I1I1I250MI1I24SIC2KKKKKKKKKKK113ACCORDINGTOTHEEXPERIMENTCONDITIONSANDEQ113KM0117MM,KI1929MM,KI2136MM,ANDS10MM,SOTHECALCULATEDIC50VALUEOFISTOBE828ΜMTHEN,ACCORDINGTOFIG5,THEEXPERIMENTALIC50VALUEIS419ΜMINTHISINVESTIGATION,THECALCULATEDIC50VALUEISABOUTTWOTIMESTHATOFTHEEXPERIMENTALONEBCALCULATIONOFIC50FORTHEMIXEDINHIBITOROZAGRELE41IMIDAZOYLMETHYLCINNAMICACID,SEESTRUCTUREINFIG2,ASASELECTIVEINHIBITOROFTHROMBOXANESYNTHASETXASINHUMANPLATELETSESPECIALLY,ISUSEDINTHETREATMENTANDPREVENTIONOFVARIOUSTHROMBOTICDISEASES13WEFOUNDTHATOZAGRELINHIBITEDMUSHROOMTYROSINASEACTIVITYTHEIC50VALUEWAS345MMOZAGRELWASESTIMATEDTOBEAREVERSIBLEMIXEDTYPEINHIBITOROFDIPHENOLASEACTIVITYWHENLDOPAWASUSEDASSUBSTRATEWITHTHECONSTANTSKS1,KS2,KI1,ANDKI2DETERMINEDTOBE221,389,0454,0799MM,REPECTIVELYTHEINHIBITIONKINETICS,ANALYZEDBYLINEWEAVERBURKPLOTS,INDICATEDOZAGRELTOBEAMIXEDINHIBITOROFDIPHENOLASEWHENLDOPAWASUSEDASSUBSTRATEITDEMONSTRATEDTHATOZAGRELBOUNDTHEENZYMEATASITEDISTINCTEDFROMTHESUBSTRATEACTIVESITE,BUTITBOUNDTOEITHEREORESFIG2STRUCTUREOFE41IMIDAZOYLMETHYLCINNAMICACIDOZAGRELINTHISTYPEOFREVERSIBLEINHIBITION,OZAGRELCANINTERACTWITHBOTHTHEFREEENZYMETYROSINASEANDTHEENZYMESUBSTRATECOMPLEXATASITEOTHERTHANTHEACTIVESITEWITHACLASSICALMICHAELISMENTENREACTIONMECHANISMESESEPKCATEISIIESIKI1KS1KS2KI2HERE,E,S,I,PDENOTEENZYMEMUSHROOMTYROSINASE,SUBSTRATELDOPA,INHIBITOROZAGREL,ANDPRODUCTDOPACHROME,RESPECTIVELY;ES,EI,ANDESIARETHERESPECTIVECOMPOUNDSASITISUSUALLYTHECASETHATSE0ANDIE0ITISASSUMEDTHATTHEEFFECTISNOTONLYONAFFINITYBUTALSOONTHERATEOFTHEBREAKDOWNOFTHEESCOMPLEX;THUSOZAGRELWOULDINFLUENCETHEENZYMEACTIVITYINTWOWAYS,AFFECTINGVMASWELLASKMITISFORMALLYCONVENIENTTOREGARDKS1,KS2,KI1ANDKI2ASTHEDISSOCIATIONCONSTANTSOFTHERESPECTIVECOMPLEXESESINTOEANDS,ESIINTOEIANDS,EIINTOEANDI,ANDESIINTOESANDI,RESPECTIVELYINTHEMICHAELISMENTENSTATE,THESUBSTRATEBINDINGSTEPANDFORMATIONOFTHEESCOMPLEXAREFASTRELATIVETOTHEBREAKDOWNRATEASISTHEUSUALLYTHECASE,THEEQUILIBRIUMEQUATIONSOFTHEENZYME,SUBSTRATE,INHIBITOR,PRODUCT,ANDTHEIRRESPECTIVECOMPOUNDSES,EI,ESIAREGIVENS1ESESK21I1EIEIK22S2EISESIK23I2ESIESIK24ACCORDINGTOEQ21TOEQ24,THERELATIONSHIPWITHKS1,KS2,KI1ANDKI2ISGIVENS1I1S2I2KKKK25THEEXPRESSIONSFORTHETOTALENZYMECONCENTRATIONANDTHEREACTIONRATETEEESEIESI26THEOVERALLVELOCITYWILLBEGIVENASFOLLOWSCATESVK27INSERTIONOFTHEEXPRESSIONSFORE,EI,ANDESIINTERMOFES,INTOTHEEXPRESSIONFORTHETOTALENZYMECONCENTRATIONGIVESS1S1TI1I2IIE1ESSSKKKK28CATTS1I1I2ESII1S1KVKKK29THERATEEQUATIONMAYBEWRITTENINTHEFORMMAXS1I1I2SII1S1VVKKK210WHICHINRECIPROCALFORMBECOMESS1I1I2MAXMAXII1111SKKKVVV⋅211ITISEVIDENTFROMEQUATION11THATTHEMIXEDTYPEINHIBITIONAFFECTSBOTHKMANDVMAXITSSPECIALCASEISNONCOMPETITIVEINHIBITIONWHICHWOULDAFFECTTHEVMAXBUTNOTTHEKMSO,THESLOPEANDINTERCEPTOFEQUATION11AREGIVENASTHEFOLLOWINGFORMS1I1MAXI1SLOPEKKV212I2MAXI1INTERCEPTKV213FORTHESTEADYSTATEMODEL,SUBSTRATEBINDINGOCCURSFASTERTHANTHEBREAKDOWNOFTHEESCOMPLEX,SOTHEKINETICFUNCTIONINTHEABSENCEOFINHIBITORISMAX0S1SSVVK214THEINHIBITIONRATIO01100VIV−MAXS1I1I2MAXS1SII1S11SSVKKKVK−215WHENIREACHES50,IIC50,SO,S15050S1I1I2S11ICIC21S1KKKK−216THEIC50VALUEISS150S1I2I1SICSKKKK217ACCORDINGTOEQ217ANDKS1,KS2,KI1,ANDKI2,THECALCULATEDIC50IS315MM,ITISVERYCLOSETOTHEEXPERIMENTALDATAOFIC50345MMIIICONCLUSIONTHEIC50VALUESOFTWONOVELTYROSINASEINHIBITORSWERECALCULATEDANDCOMPAREDTHECALCULATEDIC50VALUEOFOZAGRELISCLOSERTHANITSEXPERIMENTALDATATHERESULTSSOFAROBTAINEDINDICATEDTHATTHEFURTHERASSAYISNEEDED,FROMNOTONLYONEASPECT,BUTFROMAWHOLEPERSPECTIVEREFERENCES1LYU,“INHIBITORYEFFECTSOFSANDR6HYDROXY2,5,7,8TETRAMETHYLCHROMAN2CARBOXYLICACIDONTYROSINASEACTIVITY,”JAGRFOODCHEMVOL51,PP23442347,20032YJKIM,JECHUNG,MKURISAWA,HUYAMA,ANDSKOBAYASHI,“NEWTYROSINASEINHIBITORS,CATECHINALDEHYDEPOLYCONDENSATES,”BIOMACROMOLECULESVOL5,PP474479,20043MJIMNEZ,SCHAZARRA,JESCRIBANO,JCABANES,ANDFGARCACARMONA,“COMPETITIVEINHIBITIONOFTYROSINASEBY4SUBSTITUTEDBENZALDEHYDES,”JAGRFOODCHEMVOL49,PP40604063,20014FGMOLINA,JLMUŇOZ,RVARN,JNRODRGUEZLPEZ,FGARCACNOVAS,ANDJTUDELA,“ANAPPROXIMATEANALYTICALSOLUTIONTOTHELAGPERIODOFMONOPHENOLASEACTIVITYOFTYROSINASE,”INTJBIOCHEMCELLBIOLVOL39,PP238252,20075LGFENOLL,MJPEŇALVER,JNRODRGUEZLPEZ,RVARN,FGARCACNOVAS,JTUDELA,“TYROSINASEKINETICSDISCRIMINATIONBETWEENTWOMODELSTOEXPLAINTHEOXIDATIONMECHANISMOFMONOPHENOLANDDIPHENOLSUBSTRATES,”INTJBIOCHEMCELLBIOLVOL36,PP235246,20046JCESPNANDHJWICHERS,“KINETICSOFACTIVATIONOFLATENTMUSHROOMAGARICUSBISPORUSTYROSINASEBYBENZYLALCOHOL,”JAGRFOODCHEMVOL47,PP35033508,19997IKUBO,IKINSTHORI,YKUBO,YYAMAGIWA,TKAMIKAWA,ANDHHARAGUCHI,“MOLECULARDESIGNOFANTIBROWNINGAGENTS,”JAGRFOODCHEMVOL48,PP13931399,20008LGFENOLL,PAGARCRUIZ,RVARN,ANDFGARCACNOVAS,“KINETICSSTUDYOFOXIDATIONOFQUERCETINBYMUSHROOMTYROSINASE,”JAGRFOODCHEMVOL51,PP77817787,20039JJXIE,KKSONG,LQIU,QHE,HHUANG,ANDQXCHEN,“INHIBITORYEFFECTSOFSUBSTRATEANALOGUESONENZYMEACTIVITYANDSUBSTRATESPECIFICITIESOFMUSHROOMTYROSINASE,”FOODCHEMVOL103,PP10751079,200710SBLI,HLNIE,YXUE,HTZHANG,CTZHANG,ANDLZHU,“KINETICSOFMUSHROOMTYROSINASEINHIBITIONBYANOVELTRIFLUOROMETHYLCONTAINING1,2,3TRIAZOLECOMPOUND,”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