FattyAcidSynthesis-RensselaerPolytechnicInstitute：脂肪酸合成-伦斯勒理工学院

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1、FattyAcidSynthesisCopyright©1999-2009byJoyceJ.Diwan.Allrightsreserved.MolecularBiochemistryIIATP-dependentcarboxylationprovidesenergyinput.TheCO2islostlaterduringcondensationwiththegrowingfattyacid.Thespontaneousdecarboxylationdrivesthecondensationreaction.Theinputtofattyacidsynthesisisacet

2、yl-CoA,whichiscarboxylatedtomalonyl-CoA.Aswithothercarboxylationreactions,theenzymeprostheticgroupisbiotin.ATP-dependentcarboxylationofthebiotin,carriedoutatoneactivesite1,isfollowedbytransferofthecarboxylgrouptoacetyl-CoAatasecondactivesite2.Acetyl-CoACarboxylasecatalyzesthe2-stepreactionb

3、ywhichacetyl-CoAiscarboxylatedtoformmalonyl-CoA.Theoverallreaction,whichisspontaneous,maybesummarizedas:HCO3-+ATP+acetyl-CoAADP+Pi+malonyl-CoABiotinislinkedtotheenzymebyanamidebondbetweentheterminalcarboxylofthebiotinsidechainandthee-aminogroupofalysineresidue.Thecombinedbiotinandlysinesid

4、echainsactasalongflexiblearmthatallowsthebiotinringtotranslocatebetweenthe2activesites.Acetyl-CoACarboxylase,whichconvertsacetyl-CoAtomalonyl-CoA,isthecommittedstepofthefattyacidsynthesispathway.Themammalianenzymeisregulated,byphosphorylationallostericcontrolbylocalmetabolites.Conformationa

5、lchangesassociatedwithregulation:Intheactiveconformation,Acetyl-CoACarboxylaseassociatestoformmultimericfilamentouscomplexes.Transitiontotheinactiveconformationisassociatedwithdissociationtoyieldthemonomericformoftheenzyme(protomer).AMPfunctionsasanenergysensorandregulatorofmetabolism.WhenA

6、TPproductiondoesnotkeepupwithneeds,ahigherportionofacell'sadeninenucleotidepoolisintheformofAMP.AMPpromotescatabolicpathwaysthatleadtosynthesisofATP.AMPinhibitsenergy-utilizingsyntheticpathways.E.g.,AMPregulatesfattyacidsynthesisandcatabolismbycontrollingavailabilityofmalonyl-CoA.Fattyacids

7、ynthesisisdiminishedbylackofthesubstratemalonyl-CoA.Asdiscussedearlier,fattyacidoxidationisstimulatedduetodecreasedinhibitionbymalonyl-CoAoftransferoffattyacidsintomitochondria.AMP-ActivatedKinasecatalyzesphosphorylationofAcetyl-CoACarboxylase.Thiscauses