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Chapter 24 · Lipid BiosynthesisChapter 24Lipid Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . .Chapter OutlineFatty acid biosynthesisBiosynthesis localized in cytosol: Fatty acid degradation in mitochondriaIntermediates held on acyl carrier protein (ACP): Phosphopantetheine group attached to serine: CoA in degradationFatty acid synthase: Multienzyme complexCarbons derived from acetyl unitsAcetyl CoA to malonyl CoA by carboxylationAcetyl unit added to fatty acid with decarboxylation of malonyl CoACarbonyl carbons of acetyl units reduced using NADPHSource of acetyl unitsAmino acids, glucoseAcetyl CoA used to produce citrateCitrate exported to cytosol: ATP-citrate lyase forms acetyl-CoA and oxaloacetateSource of NADPHOxaloacetate utilizationOxaloacetate (from citrate) to malate: NADH dependent reactionMalate to pyruvate: Malic enzyme: NADPH producedPentose phosphate pathwayMalonyl-CoA production: Acetyl-CoA carboxylaseBiotin-dependent enzymeATP drives carboxylationEnzyme regulationFilamentous polymeric form activeCitrate favors active polymerPalmitoyl-CoA favors inactive protomer (polymer’s monomer or building block molecule)Citrate/palmitoyl-CoA effects depend on state of phosphorylation of proteinoUnphosphorylated protein binds citrate with high affinity: ActivationoPhosphorylated protein binds palmitoyl with high affinity: InactivationAcetyl transacetylase: Acetylates acyl carrier protein (ACP): Destined to become methyl end of fatty acidMalonyl transacetylase: Malonylates ACP-Ketoacyl-ACP synthase (acyl-malonyl ACP condensing enzyme): Accepts acetyl group: Transfers acyl group to malonyl-ACPMalonyl carboxyl group released: Decarboxylation drives synthesis128
Chapter 24 · Lipid BiosynthesisMalonyl-ACP converted to acetoacetyl-ACP-Ketoacyl-ACP reductaseCarbonyl carbon reduced to alcoholNADPH provides electrons-Hydroxyacyl-ACP dehydratase: Elements of water removed: Double bond created2,3-trans-Enoyl-ACP reductaseDouble bond reducedNADPH provides electronsSubsequent cycles: C-16: Palmitoyl-CoAAdditional modificationsElongationMitochondrial-based system uses reversal of -oxidationEndoplasmic reticulum-based system uses malonyl-CoAMonounsaturation: One double bondBacteria: Oxygen-independent pathway: Chemistry performed on carbonyl carbonEukaryotes: Oxygen-dependent pathwayPolyunsaturationPlants can add double bonds between C-9 and methyl endAnimalsAdd double bonds between C-9 and carboxyl endRequire essential fatty acids to have double bonds closer to methyl endRegulationMalonyl-CoA inhibition of carnitine-acyl transferase: Blocks fatty acid uptakeCitrate/palmitoyl regulation of acetyl-CoA carboxylaseComplex lipidsGlycerolipids: Glycerol backboneGlycerophospholipidsTriacylglycerolsSphingolipids: Sphingosine backbonePhospholipidsSphingolipidsGlycerophospholipidsGlycerolipid biosynthesis