7 11 15 Fatty Acid Synthesis Biochemistry 401 ACP Lecture 27 ACP Condensation Additional topics in Fatty Acid Oxidation Catabolism of Odd Numbered Fatty Acids ACP Reduction ACP Peroxisomes Dehydration Glyoxylate CycleFatty Acid Synthesis ACP Synthesis of Saturated Fatty Acids Reduction Synthesis of Unsaturated Fatty Acids Regulation of Fatty Acid Metabolism ACP Activated acyl group lengthened by 2C What about fatty acids with odd numbers of carbons Fatty acid catabolism proceeds as normal until at the last round of oxidation a 3C fatty acid propionyl CoA remains Propionyl CoA is used to synthesize succinyl CoA in three steps Racimization Carboxylation 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 Rearrangement by Methylmalonyl CoA Mutase 1 7 11 15 Cobalamin is a large complex ring structured prosthetic group that contains cobalt It is used in reactions that involve difficult rearrangements of configuration 4 Pyrrole Rings The 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 2 7 11 15 Formation of Succinyl CoA from Methylmalonyl CoA 1 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 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 ER Many enzymes are found there Many reactions that result in the production of peroxides H2O2 occur there In mammals long chain FA are catabolized here to shorter octanoyl CoA chains 3 7 11 15 Changing Gears Fatty Acid Synthesis Occurs in cytosol not mitochondrion One polypeptide with many enzyme functionalities Not 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 Fatty Acid Synthesis Occurs in the Cytoplasm 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 4 7 11 15 Oxidation Hydration Oxidation Thiolysis Reduction Dehydration Reduction Condensation 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 Fatty Acid Synthesis ACP ACP Condensation ACP Reduction ACP Dehydration ACP Reduction ACP Activated acyl group lengthened by 2C 7 Rounds to yield a 16C FA then thiolysis 5 7 11 15 Step1 Carboxylation of Acetyl CoA to Form 3C Malonyl CoA Enzyme Acetyl CoA Carboxylase Requires ATP Biotin biotin carries carbons generally CO2 First committed step Protein Structure of Mammalian Fatty Acid Synthase Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 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 ACP a a b Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org b 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER 6 7 11 15 2 Ketoacyl Synthase KS Condensation reaction decarboxylation of Malonyl ACP Condensation with acyl group Elongated ketoacyl ACP is formed a a b a a b CO2 CO2 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org 3 Ketoacyl ACP reductase KR First reduction NADPH is used Hydroxyacyl ACP is formed H H 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org 4 Hydroxyacyl ACP Dehydratase DH A E Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org Dehydration Enoyl ACP is formed A E 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER 7 7 11 15 5 Enoyl ACP Reductase ER Reduction two NADPH is used Acyl ACP is formed A A 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org 1 MalonylAcyl transferase MAT A Elongated acyl group Cys in KS b New malonyl group ACP A A b Timm Maier Marc Leibundgut Nenad Ban 5 SEPTEMBER 2008 VOL 321 SCIENCE www sciencemag org b 1 MalonylAcyl transferase MAT 2 Ketoacyl Synthase KS 3 Ketoacyl ACP reductase KR 4 Hydroxyacyl ACP Dehydratase DH 5 Enoyl ACP Reductase ER KS Acetyl Cys Malonyl ACP MalonylAcyl transferase MAT 8 7 11 15 Ketoacyl Synthase KS 4 Carbon Ketoacyl ACP Ketoacyl ACP Ketoacyl ACP reductase KR One Hydroxyacyl ACP Hydroxyacyl ACP Hydroxyacyl ACP Dehydratase DH Enoyl ACP 9 7 11 15 Enoyl ACP Enoyl ACP Reductase ER Two 4 Carbon saturated acyl ACP The thiolase TE activity of fatty acid synthase releases 16 C palmitate from the acyl carrier protein Step1 First committed step Carboxylation of Acetyl CoA to Form 3C Malonyl CoA Enzyme Acetyl CoA Carboxylase Requires ATP Biotin biotin carries carbons generally as HCO3 Positively Regulated by citrate Negatively
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