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Transcript
FattyAcidMetabolism Dr.KevinAhern All Reactions Occur Between α and β Carbons β-carbon FattyAcidMetabolism • Fatty Acid Oxidation - Beta Oxidation • Enzymes in Mitochondria and Peroxisomes • Generates More ATP Per Carbon Than Sugars • Proceeds 2 Carbons at a Time β α α-carbon FattyAcidMetabolism • Preparation for Oxidation • Before Oxidation, Fatty Acids Must be Activated and Transported to the Mitochondrion. • Activation Begins in the Cytoplasm Long Chain Fatty Acyl-CoA Ligase Fatty Acid Fatty Acyl-CoA • To Move the Acyl-CoA into the Mitochondrion, the CoA is Swapped with a Molecule of Carnitine Four Steps in Fatty Acid Oxidation FattyAcidMetabolism • Beta Oxidation - Reaction 1 • Oxidation Creates Trans Intermediate • Unrelated to Trans fat • Three forms of Enzyme • Medium Form Problem in SIDS Used to Generate ATP in Oxidative Phosphorylation β α FattyAcidMetabolism • Beta Oxidation Reaction 2 • Similar to Fumarase Reaction of Citric Acid Cycle • Preparation for Next Oxidation Step β β α α FattyAcidMetabolism • Beta Oxidation Reaction 3 • Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle Used to Generate ATP in Oxidative Phosphorylation β β α α FattyAcidMetabolism • Beta Oxidation Reaction 4 • Thiolase Enzyme Catalyzes the Reverse Reaction When the R-Group is a Hydrogen - Important for Ketone Body Synthesis Oxidized in Citric Acid Cycle β α Shortened by 2 Carbons FattyAcidMetabolism • Fatty Acid Oxidation - Summary • In Summary - Each Round of Oxidation Creates One FADH2, One NADH, one Acetyl-CoA, and a Fatty Acid Shortened by Two Carbons • Each Acetyl-CoA Released in Matrix of Mitochondrion Where it is Readily Oxidized in the Citric Acid Cycle. Similarity of Fatty Acid Oxidation and Citric Acid Cycle Unsaturated Fatty Acid Oxidation Unsaturated Fatty Acid Oxidation 1 2 3 4 Unsaturated Fatty Acid Oxidation 1 2 3 4 1 2 3 4 Unsaturated Fatty Acid Oxidation 1 2 3 4 Unsaturated Fatty Acid Oxidation Unsaturated Fatty Acid Oxidation FattyAcidMetabolism • Other Fatty Acid Oxidation 1. Long Chain Fatty Acids (20-22 Carbons or Greater) are Oxidized in Beta Oxidation Reactions in Peroxisomes 2. Fatty Acids with Odd Numbers of Carbons and some Amino Acids are Oxidized in β-οxidation, Yielding Propionyl-CoA Oxidation Synthesis Fatty Acid Synthesis vs Oxidation FattyAcidMetabolism • Fatty Acid Synthesis - Regulation • Located in Cytoplasm • Feedback Inhibition by Long Chain Fatty Acids • Polymerization of Enzyme Favors Activation FattyAcidMetabolism • Fatty Acid Synthesis • Remaining Catalysis Starting Here Occurs in Fatty Acid Synthase Complex 1. Replacement of CoA with Acyl Carrier Protein (ACP) ACP CoASH Transacylase Malonyl-CoA Malonyl-ACP ACP CoASH Transacylase Acetyl-CoA Acetyl-ACP FattyAcidMetabolism • Fatty Acid Synthesis 2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain 3-Ketoacyl ACP Synthase FattyAcidMetabolism • Fatty Acid Synthesis 3. Reduction of Ketone on Beta Carbon OH is in D-Configuration, in Contrast to L-Form in Beta Oxidation 3-Ketoacyl ACP Reductase FattyAcidMetabolism • Fatty Acid Synthesis 4. Removal of Water, Creating a Trans Double Bond 3-Hydroxyacyl ACP Dehydrase FattyAcidMetabolism • Fatty Acid Synthesis 5. Reduction of Double Bond Fatty Acid has Grown by 2 Carbons and Becomes Template for Next Cycle Enoyl ACP Reductase Cycle of 2 Carbon Additions Continues Until 16 Carbons Reached - Palmitic Acid FattyAcidMetabolism • Fatty Acid Synthesis 6. Release of Palmitic Acid at End of Cycle Thioesterase Palmitic Acid ACP Palmitoyl-ACP 1. Replacement of CoA with Acyl Carrier Protein (ACP) FattyAcidMetabolism • Fatty Acid Synthesis 2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain FattyAcidMetabolism • Fatty Acid Synthesis 3. Reduction of Ketone on Beta Carbon FattyAcidMetabolism • Fatty Acid Synthesis 4. Removal of Water, Creating a Trans Double Bond FattyAcidMetabolism • Fatty Acid Synthesis 5. Reduction of Double Bond FattyAcidMetabolism • Fatty Acid Synthesis 6. Release of Palmitic Acid at End of Cycle FattyAcidMetabolism • Fatty Acid Synthesis FattyAcidMetabolism • Other Fatty Acid Syntheses 1. Fatty Acids Longer than 16 Carbons are Made in the Endoplasmic Reticulum and the Mitochondrion 2. Unsaturated Fatty Acids are Made by Desaturases Found in the Endoplasmic Reticulum 3. Linoleic Acid (double bonds at #9 & 12) and Linolenic Acid (double bonds at #9, 12, & 15) are Essential Fatty Acids in Humans Mammalian Desaturates Can’t Make Double Bonds Past Position Delta #9 Prostagen, Thromboxane, and Leukotriene Synthesis Common Location of Arachidonic Acid Prostagen, Thromboxane, and Leukotriene Synthesis Synthesis of Some Prostaglandins Obesity Females Males Obesity and Hunger Adipokines - Peptide Hormones in Adipocytes Leptin - Hunger suppressor Adiponectin - Regulate glucose levels, FA oxidation Resistin - Increased inflammation, insulin resistance Effects of leptin countered by ghrelin Leptin The mouse on the left is deficient in leptin