Fatty Acid Metabolism - Oregon State University Fatty Acid Metabolism • Preparation for...

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Transcript of Fatty Acid Metabolism - Oregon State University Fatty Acid Metabolism • Preparation for...

  • Fatty Acid Metabolism

    Dr. Kevin Ahern

  • α β

    Fatty Acid Metabolism • Fatty Acid Oxidation - Beta Oxidation

    • Enzymes in Mitochondria
 and Peroxisomes

    • Generates More ATP Per Carbon 
 Than Sugars

    • Proceeds 2 Carbons at a Time

    α-carbonβ-carbon

    All Reactions Occur Between α and β Carbons

  • Fatty Acid Metabolism • 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

  • Fatty Acid Metabolism • Beta Oxidation - Reaction 1

    α

    β

    • Oxidation Creates Trans Intermediate • Unrelated to Trans fat • Three forms of Enzyme • Medium Form Problem in SIDS

    Used to Generate ATP in Oxidative Phosphorylation

  • Fatty Acid Metabolism • Beta Oxidation Reaction 2

    α

    β

    α

    β

    • Similar to Fumarase Reaction of Citric Acid Cycle • Preparation for Next Oxidation Step

  • Fatty Acid Metabolism • Beta Oxidation Reaction 3

    α

    β

    α

    β

    • Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle

    Used to Generate ATP in Oxidative Phosphorylation

  • Fatty Acid Metabolism • Beta Oxidation Reaction 4

    α

    β

    • Thiolase Enzyme Catalyzes the Reverse Reaction When the 
 R-Group is a Hydrogen - Important for Ketone Body Synthesis 


    Shortened by 2 Carbons

    Oxidized in Citric Acid Cycle

  • Fatty Acid Metabolism • 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

  • Fatty Acid Metabolism • 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

  • Fatty Acid Synthesis vs Oxidation

    Sy nt

    he si

    s Oxidation

  • Fatty Acid Metabolism • Fatty Acid Synthesis - Regulation

    •Located in Cytoplasm •Feedback Inhibition by Long Chain Fatty Acids •Polymerization of Enzyme Favors Activation

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    •Remaining Catalysis Starting Here Occurs in Fatty Acid Synthase Complex

    1. Replacement of CoA with Acyl Carrier Protein (ACP)

    Malonyl-CoA Malonyl-ACP

    ACP CoASH

    Transacylase

    Acetyl-CoA Acetyl-ACP

    ACP CoASH

    Transacylase

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain

    3-Ketoacyl ACP Synthase

  • 3-Ketoacyl ACP Reductase

    Fatty Acid Metabolism • Fatty Acid Synthesis

    3. Reduction of Ketone on Beta Carbon

    OH is in D-Configuration, in Contrast to L-Form in Beta Oxidation

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    4. Removal of Water, Creating a Trans Double Bond

    3-Hydroxyacyl ACP Dehydrase

  • Enoyl ACP Reductase

    Fatty Acid Metabolism • Fatty Acid Synthesis

    5. Reduction of Double Bond

    Cycle of 2 Carbon Additions Continues Until 16 Carbons Reached - Palmitic Acid

    Fatty Acid has Grown by 2 Carbons and Becomes Template for Next Cycle

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    6. Release of Palmitic Acid at End of Cycle

    Palmitoyl-ACP

    Palmitic Acid

    ACP

    Thioesterase

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    1. Replacement of CoA with Acyl Carrier Protein (ACP)

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    3. Reduction of Ketone on Beta Carbon

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    4. Removal of Water, Creating a Trans Double Bond

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    5. Reduction of Double Bond

  • Fatty Acid Metabolism • Fatty Acid Synthesis

    6. Release of Palmitic Acid at End of Cycle

  • Fatty Acid Metabolism • 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

  • Females

    Males

    Obesity

  • 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