Fatty Acid Metabolism - Oregon State UniversityFatty Acid Metabolism • Preparation for Oxidation...
Transcript of Fatty Acid Metabolism - Oregon State UniversityFatty Acid Metabolism • Preparation for Oxidation...
FattyAcidMetabolism
Dr.KevinAhern
αβ
FattyAcidMetabolism• Fatty Acid Oxidation - Beta Oxidation
• Enzymes in Mitochondriaand 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
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
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
FattyAcidMetabolism• Beta Oxidation Reaction 2
α
β
α
β
• Similar to Fumarase Reaction of Citric Acid Cycle • Preparation for Next Oxidation Step
FattyAcidMetabolism• Beta Oxidation Reaction 3
α
β
α
β
• Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle
Used to Generate ATP in Oxidative Phosphorylation
FattyAcidMetabolism• 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
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 23 4
Unsaturated Fatty Acid Oxidation
1 23 4
12 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
Fatty Acid Synthesis vs Oxidation
Synt
hesi
s 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)
Malonyl-CoA Malonyl-ACP
ACP CoASH
Transacylase
Acetyl-CoA Acetyl-ACP
ACP CoASH
Transacylase
FattyAcidMetabolism• Fatty Acid Synthesis
2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain
3-Ketoacyl ACP Synthase
3-Ketoacyl ACP Reductase
FattyAcidMetabolism• Fatty Acid Synthesis
3. Reduction of Ketone on Beta Carbon
OH is in D-Configuration, in Contrast to L-Form in Beta Oxidation
FattyAcidMetabolism• Fatty Acid Synthesis
4. Removal of Water, Creating a Trans Double Bond
3-Hydroxyacyl ACP Dehydrase
Enoyl ACP Reductase
FattyAcidMetabolism• 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
FattyAcidMetabolism• Fatty Acid Synthesis
6. Release of Palmitic Acid at End of Cycle
Palmitoyl-ACP
Palmitic Acid
ACP
Thioesterase
FattyAcidMetabolism• Fatty Acid Synthesis
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• 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