Download Fatty Acid Metabolism - Oregon State University

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