GlutamicO-MethylGlutamate谷氨酸鹽Methylesterificationofthesidechainofglutamicacidresidues(Figure9a)isanessentialcomponentoftheregulationofbacterialchemotaxissensoryTheesterificationiscatalyzedbyspecificL-glutamylprotein-methyltransferasesinE.coliandS.iyphimuriumusingS-adenosylmethionine腺苷甲硫氨酸asamethyldonor,itisreversedbyspecificO-ADP-ribosylFormation:HistonesH1andH2B,andtoalesserextentnonhistonechromosomalproteins,areADP-ribosylatedonthesidechainofglutamicacidresiduesbypoly(ADP-ribose)synthetase,whichisalsoasubstrate.Function:Theformationandhydrolysisofthepoly(ADP-ribose)isdynamicallyregulated,dependentuponthepresenceofsingle-ordouble-strandedbreaksinthechromatinDNA,andthefunctionofthismodificationappearstobetoopenupthestructureofchromatintoallowaccesstorepairenzymes.Thestructureofpoly(ADP-ribose)：Thestructureofpoly(ADP-ribose)isheterogeneousandincludesbranchingchains(Figure5c).-2)D-ribofuranoside核糖呋喃糖苷-CarboxyglutamicAcid1).Carboxylationofanumberofglutamicacidresiduesinspecificsequencesinseveralblood-clottingplasmaglycoproteinsisessentialfortheiractivity。Formation:AvitaminK-dependentcatalyzesthecarboxylationFunction:Themodificationresultsinincreasedcalciumionbindingaffinity,andassociatedbiologicalactivitiesoftheseproteins,whichincludeprothrombin凝血素,blood-clottingfactorsVllXandXIproteinCproteinS,andproteinZ.Appearance:AlloftheGlaresiduesarelocatedwithintheN-terminal42residues,whichareofsimilarsequenceintheseproteins.2)Carboxyglutamicacidresiduesarealsofoundinotherproteins,includingsomeinvolvedincalcification石灰化,suchasosteocalcinandribosomalprotein.Feature:Theside-chainstructureisthermallyunstable,undergoingdecarboxylationtogivetheglutamicacidsidechain.AglutamicacidresidueneartheC-terminusofmousebraintubulin(Glu-445)ismodifiedbytheadditionofaheterogeneousnumberofglutamylunits.Structure:Amoredetailed ysisofthestructures(Figure9c)showedthatfromonetosixormoreglutamylresiduesarepresent,andthatwhereasthefirstresidueisamidebondedtothe-carboxylgroupofGlu-445,thesecondandthirdarelinkedby-carboxylpeptideFunction:Thismodification,whichcontributestothehighdegreeofheterogeneityofbraintubulinasdeterminedbyisoelectricfocusing,isprobablyimportantinregulatingmicrotubuleβ-Hydroxy-β-carboxyglutamicAcid(AminoCitricThisunusualaminoacidwasidentifiedinanacidhydrolysateofcalfthymusnucleoprotein(WilhelmandKupka,1981EthanolamineispresentinamidelinkagetothesidechainsofGlu-30landGlu-374inmurineEF-la;thehydroxylgroupsaremodifiedbytheadditionofaphosphoglycerylunit(Figure9f)(Whiteheartetal.,1989).CoenzymeAThiolGlutamicacid-344inpigheartCoAtransferaseistransientlythioesterifiedbyduringcatalysis(RochetandBridger,1DeamidationtoGlutamicUnderphysiologicalconditions,thehydrolyticdeamidationofglutaminesidechainsinsmallpeptideswasdeterminedtooccurwithhalf-livesintherangeof96-3400days.ThepresenceofneighboringgroupsinfoldedproteinstructuresmayincreaseordecreasetherateofTransamidationtoformN-(-Theformationofcross-linkingofpeptideAwidespreadformofcross-linkingofpeptidechainsinproteinsistransamidationbydisplacementoftheamideNH2groupbythe-aminogroupoflysineresidues,catalyzedbyThefeatureofcross-linkingofpeptideTheisopeptidebondformedhasachemicalstabilitysimilartothatofthepeptideOnetransglutaminaseactivityresidesinblood-clottingfactorXllla;theadditionofcross-linksbetweenfibrinandotherproteinsintheinitiallyformedclotyieldsafirmer,morestableclot.Othertransglutaminasesarelocatedinepidermal表皮tissueandhairfollicles ,andfunctiontocross-linkskinandhairproteins.Inmusclecells,reversibleformationofGlu-Lyscross-linksisobserved,across-linkedintracellularmatrix,insolublein6Mguanidiniumchloride,hasbeendescribed.N5-MethylglutamineispresentinE.coliribosomalproteinL3;itisimportantintheassemblyofribosomes.Thesameresidueisformedinvitrobytreatmentof2-macroglobulinwithmethylamine:thethiolesterbondisreactivetonucleophiles.ThiolTheoccurrenceofathiolesterbondbetweenaglutaminylsidechainandacysteinylsidechainin2-macroglobulinandsomecomplementproteinsisdiscussedabove.Asdiscussedabove,glutamineresiduesattheamino-terminusofproteinsaregenerallyconvertedeitherenzymicallyorspontaneouslytopyrrolidonecarboxylAfreeradicalderivedfromGly-734ispresentinE.colipyruvateformate-lyase 解酶(Wagneretal.,1992)andpossiblyinarelatedsequencewithinanaerobicribonucleotide e(Sunetal.,1993).MethylN-Methylhistidine(Figure10a)ispresentinthemuscleproteinsmyosinandactin,andinavian鳥類erythrocytehistonefractionsIandVandbovineopsinN-Methylhistidine(Figure10b)hasalsobeenidentified,His157inrabbitskeletalmusclemyosinlight-chainN-PhosphorylPhosphohistidineresidues(Figure10candd)havebeenlocatedinavarietyFeature:TheN-Pbondisunstable,especiallyunderacidicconditions,andphosphohistidineisoftentransientlyformedinvivo,attheactivesitesofsomeenzymes.TheseenzymesincludeE.colisuccinatethiokinase琥珀酸硫激酶,nucleoside核苷diphosphatekinasefromvarioussources,withbothN-andN-isomers,phosphoglyceratemutase磷酸甘油變位酶,adrenocortical腎上腺皮質(zhì)的cyclicnucleotide-independentproteinkinase,SPK380(N-isomer),enzymeIofthe 酸:glycosephosphotransferasesystemofSalmonellatyphimurium沙門氏菌(N)andnitrogenregulatorI(NR1)ofE.coli.PhosphohistidineisalsopresentinmyelinbasicproteinandratliverhistoneHistidine-specificnuclearproteinkinaseshavebeenNDPkinaseisamultifunctionalenzymethatappearstoactasahistidinekinaseandassuch,toregulatetheactivationofsomeG-proteins.HistoneH4histidinekinaseactivityhasbeenshowntocorrelatewithcellularproliferationandthereisevidencethatitisanoncodevelopmentalmarkerinThefieldofmammalianhistidinekinaseresearchisstillverymuchinitsinfancy,butasmethodsfordetectionofphosphohistidine-containingproteinsandassaysforhistidinekinasesimprove,thetrueimportanceoftheseenzymesinmammaliancellregulationislikelytoberevealedinthenearfuture.(PaulG.Besant,PaulV.Attwood,Mammalianhistidinekinases.BiochimicaetBiophysica1754(2005)281–Iodohistidine碘組氨Smallamountsof4-iodohistidine(Figure10e),detectedfollowingradiolabelinginvivoarepresentinThechemicaliodinationofproteinsorinvitroactionofthyroid甲狀腺peroxidaseyieldslargeramounts(Nearyetal.,1984).8-HistidylFlavin黃素，四羥ManyoxidasesanddehydrogenasescontainandinahighproportionoftheseFADislinkedtoahistidinesidechainthroughanalkyl烷基bondtothe8-methylgroup.Examplesofflavoproteins黃素蛋白with8-N-histidyl-FADarethiamine硫胺dehydrogenasefromasoilbacteriumandL- 糖酸內(nèi)酯oxidasefrommammalianliver.FlavoproteinswiththeN-linkedisomerincludesuccinate琥珀酸dehydrogenase,sarcosine肌氨酸一oxidasefromvarioussources.Diphthamide白喉Appearance:Araremodificationofhistidinesidechains,diphthamide,thetrivialnamefor2-[3-carboxamide氨甲酰-3-(trimethylammonio 基)propyl丙基]histidine(Figure10g),islocatedineukaryoticelongationfactorII.ItisthesiteforADP-ribosylationbydiphtheriatoxinPseudomonas假單胞菌屬exotoxinA,andananimaltransferase.TheADP-riboseisattachedtoNoftheimidazolegroupofdiphthamideviaana-glycosidic糖苷linkage(Figure10h).Function:Thefunctionofthediphthamideresidueisunknown,butADP-ribosylationleadstoinhibitionofthefunctionofEF-2,andtheendogenousADP-ribosyltransferasemayregulateproteinsynthesis.(Allysinealdol醛縮賴氨酸丁間酮醛Thehistidinesidechaincantakepartintheformationofcrosslinksbetweenpolypeptidechainsfollowingoxidativedeaminationofsidechainsoflysineresidues(seepage61).3.8.7.Appearance:AsecondforminproteinsishistidinoalanineorN-(2-(Figure10ifirstidentifiedindentin象andbone,andsubsequentlyinphosphoserineandasparticacid-richcalcium-bindingproteins,etc.Formation:Thecross-linkisformedviaalkylationofintermediatedehydroalanineresiduesderivedfromphosphoserineresidues.S-(2-Thisunusualcross-linkinggroupFigure8jispresentinNeurosporacrassa泳胞菌tyrosinase(Lerch,1982,1984).Light-orfree-radical-catalyzedoxidationofhistidineresiduesisacommoninvitrodegradativereactionandcanoccur,forexample,inthecopper(II)catalyzedautoxidationofglycatedproteins.2).OxidationofE.coliglutaminesynthetaseatasinglehistidineresiduemayoccurinvivo,inactivatingtheenzymeandrenderingitsusceptibletoproteolyticdegradation.3).Cu,Zn-Superoxidedismutaseisresidue118.Acylationofthee-AminoN-Acetyl-lysine.Side-chainacetylation(Figure11a)ofnuclearproteinsonlysineresiduesiscommon.Example:1).Severalchromosomalproteinsareextensivelyacetylatedinareversibleprocess,includinghistonesH3(Lys-9,14,18and23),H4(Lys-5,8,12and6),HMG1(Lys-2and11),HMG14(Lys-2and4),andHMG17(Lys-2,4and10)acetylatedatalysinesideLysineacetylationhasemergedasamajorposttranslationalmodificationforhistones.Crossregulationbetweenthisandothermodificationsiscrucialinmodulatingchromatin-basedtranscriptionalcontrolandsha inheritableepigeneticprograms.Inadditiontohistones,manyothernuclearproteinsandvariouscytoplasmicregulatorsaresubjecttolysineacetylation.YangXJ,SetoE.Lysineacetylation:codifiedcrosstalkwithotherposttranslationalmodifications.MolCell.2008Aug22;31(4):449-61..Fattyacylation.Palmitoylationoflysineresiduesinthebacterialtoxinsadenylate腺苷酸cyclaseof lapertussis百日咳桿菌(Lys-983)andhemolysinofEcoli(Lys-564and690N-biotinyllysine.Theimportantenzymecofactor,biotin,whichservesasaCO2carrierincarboxylases, transcarboxylases,anddecarboxylases,suchaspyruvatecarboxylaseandacetyl-CoAcarboxylase(Knowles,1989),islinkedthroughanamidebondbetweenthecarboxylgroupofbiotinandNofalysineresidueintheenzyme(Figure11b).inconservedportionsofseveraloftheseenzymesN-lipoyllysine.硫辛酰賴氨酸Thelipoate硫辛酸acetyltransferchainsofthepyruvatedehydrogenasemultienzymecomplexofE.colicontaintwoThelipoicacid硫辛酸 courseoftheenzymicreactionThesecross-linkinggroupsarediscussedabove(seepages37andMurein胞壁質(zhì),thepolysaccharide-peptidecellwallmaterial,isattachedthroughtheopticalL-centerofadiaminopimelicacid二氨基庚二酸residueFigure11dtotheε-aminogroupoftheC-terminallysineresidueoftheE.colioutermembranelipoproteinManyintracellularproteinsaretargetsforthetransferofubiquitin,activatedasathiolesterinaubiquitin-carrierproteincomplex, toformamidebondsbetweentheC-terminal(Gly-76)-carboxylgroupofubiquitinandcertainlysinesidechains.polyubiquitinchains.UbiquitinylationmarksproteinsforN-Phosphoryl-lysine(Figure11f)ispresentinratliverhistoneHIandATP-treatednucleosidediphosphatekinasefrombovineliverandhumanerythrocytes.AldehydeCondensationProducts乙醛濃縮light-absorbingpigmentofrhodopsin視紫質(zhì)isboundasaSchiffbase(Figure11g)inHalobacteriumhalobiumrhodopsinatLys-216,andinbovinerhodopsinatLys-296.Appearance:ManyenzymesofaminoacidmetabolismcontainthecoenzymepyridoxalphosphateboundthroughtheformylgroupinaSchiffbasetotheNofalysineresidue(Figurellh).glutamatedecarboxylase,andserineThefunctionoftheboundpyridoxalphosphateistoformSchiffbaseswithsubstrates,leadingtolabilizationofbondsatthe-carbonoftheaminoacidsubstratecomplex.bindingofreducingsugarstoaminogroupsinNonenzymicinvivobindingofreducingsugarstoaminogroupsinproteinsisawidespreadphenomenonthatisparticularlyimportantinlong-livedproteins,suchaslenscrystallinsandconnectivetissueproteins,andiselevatedindiabetes1-Deoxy-l-(N-lysine)fructose,formedbyAmadorirearrangementoftheinitiallyformedaldimineadductofglucose(Figure11i),hasbeendeterminedinserumGlycationmayhavedeleteriouseffectsontheactivitysomeenzymes,suchasglutathione谷胱甘肽 eAslowreactionofAmadoriproductstoformaofcross-linkedadvancedglycationendtypicallypyrroles四氫吡咯andimidazolesisimplicatedinpathology.Productsofoxidationofglycated1).OneproductofoxidationofglycatedproteinsisN-carboxymethyllysine,whichalsoarisesfromthereactionofproductsofautoxidationofascorbatewith2).Anotherproduct.formedthroughcross-linkingbypentose戊糖withanarginineresidueispentosidineAwidevarietyofstructuresariseinextracellularstructuralproteinsincludingcollagenandelastinfollowingenzyme-catalyzedhydroxylationandoxidativedeaminationoflysineresidues.Thenatureandproportionofthecross-linkingstructuresvarywiththetissueandtheageofanimalAnimportantmodificationofcollagenprecursorsandcollagen-likesequencesinproteinssuchascomplement ClqisthehydroxylationofmanylysineTheseresidues(Figurellv)maysubsequentlytakepartinoxidativedeaminationandcross-linking(seeabove).TheymayalsobeO-glycosylated,forexample,inrenal腎glomerular腎小球basementmembraneprotein,mosthydroxylysineresiduesbearadisaccharideunit(glucosyl-galactosyl)in linkagetohydroxylysine.MethylatedlysineAppearance:1ThreeN-methylatedderivatives(mono-,diandtrimethyllysine)oflysine(Figurellw)havebeenfoundinproteinsofvariouskinds,includinghistones,ribosomalproteins,elongationfactors,calmodulin調(diào)鈣蛋白,myosin,andcytochromecN-Trimethyl--hydroxylysineanditsphosphateesterwerefoundindiatomEffects:TheeffectsofmethylationofcytochromechavebeenstudiedinAlthoughmethylationdoesnotalterthechargeonthesidechainatneutralpH,hydrogenbondingcapabilityislost,andthiscanleadtoconformationalchangesresultinginchangesinphysicochemicalandbiologicalproperties.Onebiologicalpropertyaffectedbymethylationoflysinesidechainsisproteolyticdegradation,includingthatthroughtheATP-ubiquitin-dependentOverthepastfewyears, ysisofhistonelysinemethylationinactiveandrepressivenuclearcompartmentsand,morerecently,genome-wideprofilingofhistonelysinemethylationindifferentcelltypeshaverevealedcorrelationsbetweenparticularmodificationsandthetranscriptionalstatusof(DambacherS,HahnM,SchottaG.Epigeneticregulationofdevelopmentbyhistonemethylation.Heredity.2010Jul;105(1):24-37.Epub2010MayHypusine,orN-(4-amino-2-hydroxybutyl羥基丁基)lysineFigurellx),anunusualaminoacidfoundinanimalproteinswaslocatedintranslationinitiationfactoreIF-5A(formerlyknownaseIF-4D）。Carbonyl碳酰基redu e/NADP+-dependentprostaglandin dehydrogenasefromhumanplacenta胎盤hasLys-238modifiedtoN6-(1-carboxyethyl)lysine(Figure11y).proposedincutinase角質(zhì)酶,butwasnotAppearancePost-translationalhydroxylationofprolineresiduestakesplaceinthecharacteristicrepeating-Gly-Xaa-Pro-unitofcollagenandrelatedextracellularstructuralandfunctionalproteinssuchascomplementcomponentClqandlungsurfactant表面活性glycoproteinSP-A.ItisimportantinstabilizingthetypicalHydroxyproline(Hyp)(Figure12a)isalsoanimportantconstituentofplantcell-wallproteins.Aglycoproteinlectinfrompotatotubershasahighcontent(16%oftheresidues)ofhydroxyproline,mostofthecarbohydrateis linkedthroughThisisomer(Figure12b)isaminorproportion(about2%))ofcalfskinhydroxyproline,butinsomecollagentypesitconstitutesasmuchas10%.Itispresentinthesequencemotif-Gly-3Hyp-4Hyp-Gly-.3,4-Dihydroxyprolineispresentindiatomcellwalls.GlycosylatedDerivativesofArabinosyl- 糖presentinpotatolectinhydroxyproline(Figure12c)andO4-galactosylhydroxyprolinearepresentinextensin伸展蛋白,theyoungextracellularmatrixglycoproteinofplantcellwalls,andinsolubleextracellular 半乳聚糖proteins.AcylFattyacylAlthoughO-palmitoylserineresidueshavebeenproposedtobepresentinsomemembrane-associatedproteinsinthoseexampleswherethesiteofpalmitoylationhasbeendeterminedthelinkagewasdescribedasbeingtocysteineorthreonine.Thusalthoughtheremaybeexamplesoffattyacylserineresiduese.gthatproposedinamutant(Cys-67~Ser)humantransferrin鐵傳遞蛋receptor)theyarerare.PhosphateO-Phosphoserine(Figure13a)isaverycommonmodification,inbothstableandreversibleforms.areexamplesofextracellularphosphoproteins,thelatterbeingveryheavilyphosphorylated.Manyeukaryoticintracellularproteinsarereversiblyphosphorylatedonserine(andthreonine)residuesbyawidevarietyofspecificproteinkinasesandphosphatasesinregulatorypathways.O-(4'Phosphopantetheine磷酸泛酰巰基Thisderivative(Figure13b)ispresentinE.coliacylcarrierproteinandinthemitochondrialelectron-transportcomplex.O-(ADP-ribosyl-Ratliverhistones,radiolabeledinvivowithNAD,incorporatedADP-riboseandphosphateonserineresidues(Figure13c).Thisphosphatediester(Figure13d)ispresentinproteinaseIfromDictyos iumdiscoideum盤Transientesterintermediatesinenzymereactions.formedasintermediatesinthehydrolysisofpeptidesandpeptideestersbytheserineproteases,suchastrypsinandAppearance:Thiscommonlinkageunitischaracteristicofanimalmucins 素,butisalsopresentinmanyotherStructure:OuterglycanchainsareoftenlinkedtothisbygalactosylorN-acetylglucosaminylgroups,andalargevarietyoflinearandbranched-chainstructureshavebeenExamplesincludeleukosialin,withpoly-N-acetyllactosaminylstructures,somecontainingsialyl唾液酸Lexterminalstructures,andhumaninterferon-2withasmall,partiallysialylatedglycanstructure.Therea