7/11/151Biochemistry401Lecture 27 Additional topics in Fatty Acid Oxidation: Catabolism of Odd Numbered Fatty Acids Peroxisomes Glyoxylate CycleFatty Acid SynthesisSynthesis of Saturated Fatty AcidsSynthesis of Unsaturated Fatty AcidsRegulation of Fatty Acid Metabolism Condensation Dehydration Reduction Reduction Activated acyl group lengthened by 2C Fatty Acid Synthesis ACPACPACPACPACPACPWhat about fatty acids with odd numbers of carbons? Fatty acid catabolism proceeds as normal until, at the last round of β-oxidation, a 3C fatty acid, propionyl-CoA, remains. Propionyl CoA is used to synthesize succinyl CoA in three steps. 1) Carbon is added in an ATP - dependent carboxylation Biotin is required (carbon carrier) 2) Racimization: D- to L-methylmanonyl CoA 3) Rearrangement of L-methylmanonyl CoA by Methylmalonyl CoA Mutase to Succinyl-CoA. Cobalamin (B12) is required for the mutase reaction Succinyl-CoA can enter the TCA cycle. Racimization Rearrangement by Methylmalonyl CoA Mutase Carboxylation7/11/152Cobalamin is a large, complex ring-structured prosthetic group that contains cobalt. It is used in reactions that involve difficult rearrangements of configuration. 4 Pyrrole RingsThe mutase reaction results in an intramolecular rearrangement of methylmalonyl CoA Cobalt allows formation of a free radical necessary for this reaction. Because of the weakness of the C-Co3+ bond in 5´-deoxyadenosylcobalamin, homolytic cleavage with radical formation occurs. The ability of cobalamin to form radicals is important for the mutase reaction.7/11/1531. Radical abstracts a hydrogen atom from the methyl group to form CH2• radical. 2. Spontaneous rearrangement of CO-S-CoA and radical. 3. Radical abstracts a hydrogen atom from 5´-deoxyadenosine to form a 5´-deoxyadenosine radical. Formation of Succinyl CoA from Methylmalonyl CoA Catabolism occurs in both the mitochondrial matrix and peroxisomes in mammals, and occurs in peroxisomes exclusively in plants and in yeast.Single membrane-bound organelle Thought to arise from the ERMany enzymes are found thereMany reactions that result in the production of peroxides,H2O2, occur there. In mammals, long chain FA are catabolized here to shorter octanoyl CoA chains.7/11/154Changing Gears: Fatty Acid Synthesis ➢ Occurs in cytosol, not mitochondrion. ➢ One polypeptide with many enzyme functionalities. ➢ Not β-oxidation in reverse. ➢ Intermediates attached to acyl carrier protein(ACP), not CoA. ➢ FA chain grows by addition of acetyl CoA. ➢ Requires a donor molecule: malonyl CoA. ➢ The addition of acetyl CoA is driven by CO2 release (Entropy). ➢ Maximum length 16C (palmitate). ➢ Any further acyl additions or double bond formations require other enzymes. Acetyl CoA cannot pass through inner mitochondrial membrane. ➢ Acetyl CoA in mitochondrion used to make to citrate ➢ Citrate transported to the cytosol ➢ Citrate reconverted to acetyl CoA and OAA in cytosol ➢ OAA converted to pyruvate for re-entry to mitochondrion. Fatty Acid Synthesis Occurs in the Cytoplasm7/11/155Reduction Dehydration Reduction Condensation Oxidation Hydration Oxidation Thiolysis ACP: The acyl carrier protein (ACP) portion of fatty acid synthase carries intermediates in FA synthesis . Phosphopantetheine group swings intermediates between functional centers in fatty acid synthase. ACP Condensation Dehydration Reduction Reduction Activated acyl group lengthened by 2C 7 Rounds to yield a 16C FA then thiolysis… Fatty Acid Synthesis ACP ACP ACP ACP ACP ACP7/11/156Step1) Carboxylation of Acetyl-CoA to Form 3C Malonyl-CoA Enzyme: Acetyl-CoA Carboxylase Requires ATP Biotin (biotin carries carbons - generally CO2) First committed step 5 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2. β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) Protein Structure of Mammalian Fatty Acid Synthase!5 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2. β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) 1.MalonylAcyl transferase (MAT) Load the reactants into the enzyme a)Acetyl CoA: ACP then Cys in (KS)b) Malonyl CoA: ACPa a b b7/11/1575 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2.β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) a a b b 2. β-Ketoacyl Synthase(KS) Condensation reaction decarboxylation of Malonyl-ACP Condensation with acyl group Elongated β-ketoacyl-ACP is formed!CO2 CO2a aβ β 5 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2.β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) β β 3. β-Ketoacyl-ACP reductase (KR) First reduction: NADPH is used Hydroxyacyl-ACP is formed !H H 5 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2.β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) 4.β-Hydroxyacyl-ACP Dehydratase (DH) Dehydration Enoyl-ACP is formed !E E A A7/11/1585 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2. β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) 5.Enoyl-ACP Reductase (ER) Reduction two NADPH is used Acyl-ACP is formed !A A 5 SEPTEMBER 2008 VOL 321 SCIENCE www.sciencemag.org!Timm Maier, Marc Leibundgut, Nenad Ban*1.MalonylAcyl transferase (MAT) 2. β-Ketoacyl Synthase (KS) 3.β-Ketoacyl-ACP reductase (KR) 4.β-Hydroxyacyl-ACP Dehydratase (DH) 5.Enoyl-ACP Reductase (ER) A A b b 1.MalonylAcyl transferase (MAT) A)Elongated acyl group: Cys in (KS)b) New malonyl group: ACPMalonyl ACPKSAcetyl-CysMalonylAcyl transferase (MAT)7/11/1594-Carbon β-Ketoacyl-ACPβ-Ketoacyl Synthase(KS) β-Ketoacyl-ACPOneβ-Hydroxyacyl-ACPβ-Ketoacyl-ACP
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