不容错过的英文版生物化学Word文档格式.docx
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不容错过的英文版生物化学Word文档格式.docx
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InbornErrorsinAminoAcidMetabolism
Introduction
Alltissueshavesomecapabilityforsynthesisofthenon-essentialaminoacids,aminoacidremodeling,andconversionofnon-aminoacidcarbonskeletonsintoaminoacidsandotherderivativesthatcontainnitrogen.However,theliveristhemajorsiteofnitrogenmetabolisminthebody.Intimesofdietarysurplus,thepotentiallytoxicnitrogenofaminoacidsiseliminatedviatransaminations,deamination,andureaformation;
thecarbonskeletonsaregenerallyconservedascarbohydrate,viagluconeogenesis,orasfattyacidviafattyacidsynthesispathways.Inthisrespectaminoacidsfallintothreecategories:
glucogenic,ketogenic,orglucogenicandketogenic.GlucogenicaminoacidsarethosethatgiverisetoanetproductionofpyruvateorTCAcycleintermediates,suchasα-ketoglutarateoroxaloacetate,allofwhichareprecursorstoglucoseviagluconeogenesis.Allaminoacidsexceptlysineandleucineareatleastpartlyglucogenic.Lysineandleucinearetheonlyaminoacidsthataresolelyketogenic,givingriseonlytoacetylCoAoracetoacetylCoA,neitherofwhichcanbringaboutnetglucoseproduction.
Asmallgroupofaminoacidscomprisedofisoleucine,phenylalanine,threonine,tryptophan,andtyrosinegiverisetobothglucoseandfattyacidprecursorsandarethuscharacterizedasbeingglucogenicandketogenic.Finally,itshouldberecognizedthataminoacidshaveathirdpossiblefate.Duringtimesofstarvationthereducedcarbonskeletonisusedforenergyproduction,withtheresultthatitisoxidizedtoCO2andH2O.
*Theaminoacidsarginine,methionineandphenylalanineareconsideredessentialforreasonsnotdirectlyrelatedtolackofsynthesis.Arginineissynthesizedbymammaliancellsbutataratethatisinsufficienttomeetthegrowthneedsofthebodyandthemajoritythatissynthesizediscleavedtoformurea.Methionineisrequiredinlargeamountstoproducecysteineifthelatteraminoacidisnotadequatelysuppliedinthediet.Similarly,phenyalanineisneededinlargeamountstoformtyrosineifthelatterisnotadequatelysuppliedinthediet.
Non-EssentialAminoAcidBiosynthesis
GlutamateandAspartate
Glutamateissynthesizedfromits'
widelydistributedα-ketoacidprecursorbyasimple1-steptransaminationreactioncatalyzedbyglutamatedehydrogenase.AsdiscussedintheNitrogenMetabolismpage,theglutamatedehydrogenasereactionplaysacentralroleinoverallnitrogenhomeostasis.
Reactionsofglutamatedehydrogenase
Likeglutamate,aspartateissynthesizedbyasimple1-steptransaminationreactioncatalyzedbyaspartateaminotransferase,AST(formerlyreferredtoasserumglutamate-oxalatetransaminase,SGOT).
Aspartatecanalsobederivedfromasparagine(whosesynthesisisoutlinedbelow)throughtheactionofasparaginase.TheimportanceofaspartateasaprecursorofornithinefortheureacycleisdescribedintheNitrogenMetabolismpage.
AlanineandtheGlucose-AlanineCycle
Asidefromitsroleinproteinsynthesis,alanineissecondonlytoglutamineinprominenceasacirculatingaminoacid.Inthiscapacityitservesauniqueroleinthetransferofnitrogenfromperipheraltissuetotheliver.Alanineistransferredtothecirculationbymanytissues,butmainlybymuscle,inwhichalanineisformedfrompyruvateatarateproportionaltointracellularpyruvatelevels.Liveraccumulatesplasmaalanine,reversesthetransaminationthatoccursinmuscle,andproportionatelyincreasesureaproduction.Thepyruvateiseitheroxidizedorconvertedtoglucoseviagluconeogenesis.Whenalaninetransferfrommuscletoliveriscoupledwithglucosetransportfromliverbacktomuscle,theprocessisknownastheglucose-alaninecycle.Thekeyfeatureofthecycleisthatin1molecule,alanine,peripheraltissueexportspyruvateandammonia(whicharepotentiallyrate-limitingformetabolism)totheliver,wherethecarbonskeletonisrecycledandmostnitrogeneliminated.
Thereare2mainpathwaystoproductionofmusclealanine:
directlyfromproteindegradation,andviathetransaminationofpyruvatebyalaninetransaminase,ALT(alsoreferredtoasserumglutamate-pyruvatetransaminase,SGPT).
Theglucose-alaninecycleisusedprimarilyasamechanismforskeletalmuscletoeliminatenitrogenwhilereplenishingitsenergysupply.Glucoseoxidationproducespyruvatewhichcanundergotransaminationtoalanine.Thisreactioniscatalyzedbyalaninetransaminase,ALT(ALTusedtobecalledserumglutamate-pyruvatetransaminase,SGPT).Additionally,duringperiodsoffasting,skeletalmuscleproteinisdegradedfortheenergyvalueoftheaminoacidcarbonsandalanineisamajoraminoacidinprotein.Thealaninethenentersthebloodstreamandistransportedtotheliver.Withintheliveralanineisconvertedbacktopyruvatewhichisthenasourceofcarbonatomsforgluconeogenesis.Thenewlyformedglucosecanthenenterthebloodfordeliverybacktothemuscle.Theaminogrouptransportedfromthemuscletotheliverintheformofalanineisconvertedtoureaintheureacycleandexcreted.
CysteineBiosynthesis
Thesulfurforcysteinesynthesiscomesfromtheessentialaminoacidmethionine.AcondensationofATPandmethioninecatalyzedbymethionineadenosyltransferaseyieldsS-adenosylmethionine(SAMorAdoMet).
BiosynthesisofS-adenosylmethionine,SAM
SAMservesasaprecurosorfornumerousmethyltransferreactions(e.g.theconversionofnorepinephrinetoepinenephrine,seeSpecializedProductsofAminoAcids).TheresultofmethyltransferistheconversionofSAMtoS-adenosylhomocysteine.S-adenosylhomocysteineisthencleavedbyadenosylhomocyteinasetoyieldhomocysteineandadenosine.Homocysteinecanbeconvertedbacktomethioninebymethioninesynthase,areactionthatoccursundermethionine-sparingconditionsandrequiresN5-methyl-tetrahydrofolateasmethyldonor.ThisreactionwasdiscussedinthecontextofvitaminB12-requiringenzymesintheVitaminspage.
TransmethylationreactionsemployingSAMareextremelyimportant,butinthiscasetheroleofS-adenosylmethionineintransmethylationissecondarytotheproductionofhomocysteine(essentiallyaby-productoftransmethylaseactivity).IntheproductionofSAMallphosphatesofanATParelost:
oneasPiandtwoasPPi.ItisadenosinewhichistransferredtomethionineandnotAMP.
Incysteinesynthesis,homocysteinecondenseswithserinetoproducecystathionine,whichissubsequentlycleavedbycystathionasetoproducecysteineandα-ketobutyrate.Thesumofthelattertworeactionsisknownastrans-sulfuration.
Cysteineisusedforproteinsynthesisandotherbodyneeds,whiletheα-ketobutyrateisfirstconvertedtopropionyl-CoAandthenviaa3-stepprocesstotheTCAcycleintermediatesuccinyl-CoA.Whilecysteinereadilyoxidizesinairtoformthedisulfidecystine,cellscontainlittleifanyfreecystinebecausetheubiquitousreducingagent,glutathione,effectivelyreversestheformationofcystinebyanon-enzymaticreductionreaction.
UtilizationofMethionineintheSynthesisofCysteine
The2keyenzymesofthispathway,cystathioninesynthaseandcystathionase(cystathioninelyase),bothusepyridoxalphosphateasacofactor,andbothareunderregulatorycontrol.Cystathionaseisundernegativeallostericcontrolbycysteine,aswell,cysteineinhibitstheexpressionofthecystathioninesynthasegene.
Geneticdefectsareknownforboththesynthaseandthelyase.Missingorimpairedcystathioninesynthaseleadstohomocystinuriaandisoftenassociatedwithmentalretardation,althoughthecompletesyndromeismultifacetedandmanyindividualswiththisdiseasearementallynormal.Someinstancesofgenetichomocystinuriarespondfavorablytopyridoxinetherapy,suggestingthatinthesecasesthedefectincystathioninesynthaseisadecreasedaffinityforthecofactor.Missingorimpairedcystathionaseleadstoexcretionofcystathionineintheurinebutdoesnothaveanyotheruntowardeffects.Rarecasesareknowninwhichcystathionaseisdefectiveandoperatesatalowlevel.Thisgeneticdiseaseleadstomethioninuriawithnootherconsequences.
Elevatedlevelsofhomocysteineinthebloodhavebeenshowntocorrelatewithcardiovasculardysfunction.Theroleofhomocysteineincardiovasculardiseaseisrelatedtoitsabilitytoinduceastateofinflammation.Homocysteineservesasanegativelychargedsurfacethatattractsthecontactphaseoftheintrinsicpathwayofbloodcoagulation.Activationoftheintrinsiccoagulationcascadeleadstoinappropriatethrombolyticeventsaswellasresultinginincreasesininflammatorycytokinereleasefromleukocytesthatareactivatedasaresultofthepro-coagulantstate.Therefore,itisimportanttoensurethatproperfunctionofthemethioninesynthasereactionismaintained.AlthoughitwouldbeassumedthatincreasedintakeofvitaminB12shouldleadtoincreasedconversionofhomocysteinetomethionine,andthusreducedlevelsofcirculatinghomocysteine,controlledstudieshaveshownthatthisdoesnotoccur.
TyrosineBiosynthesis
Tyrosineisproducedincellsbyhydroxylatingtheessentialaminoacidphenylalanine.Thisrelationshipismuchlikethatbetweencysteineandmethionine.Halfofthephenylalaninerequiredgoesintotheproductionoftyrosine;
ifthedietisrichintyrosineitself,therequirementsforphenylalaninearereducedbyabout50%.
Phenylalaninehydroxylaseisamixed-functionoxygenase:
oneatomofoxygenisincorporatedintowaterandtheotherintothehydroxyloftyrosine.Thereductantisthetetrahydrofolate-relatedcofactortetrahydrobiopterin,whichisma
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