1. Fatty Acid Metabolism
Dr. Kevin Ahern

2. All Reactions Occur Between α and β Carbons
Fatty Acid Metabolism α β
Fatty Acid Oxidation - Beta Oxidation
Enzymes in Mitochondria and Peroxisomes
Generates More ATP Per Carbon Than Sugars
Proceeds 2 Carbons at a Time

3. Long Chain Fatty Acyl-CoA Ligase
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

4. To Move the Acyl-CoA into the Mitochondrion, the CoA is Swapped with a Molecule of Carnitine

5. Four Steps in Fatty Acid Oxidation

6. Used to Generate ATP in Oxidative Phosphorylation
Fatty Acid Metabolism
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 α β

7. Fatty Acid Metabolism
Beta Oxidation Reaction 2
Similar to Fumarase Reaction of Citric Acid Cycle
Preparation for Next Oxidation Step α β α β

8. Used to Generate ATP in Oxidative Phosphorylation
Fatty Acid Metabolism
Beta Oxidation Reaction 3
Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle
Used to Generate ATP in Oxidative Phosphorylation α β α β

9. Fatty Acid Metabolism
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
Shortened by 2 Carbons α β

10. 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.

11. Similarity of Fatty Acid Oxidation and Citric Acid Cycle

12. Unsaturated Fatty Acid Oxidation

13. Unsaturated Fatty Acid Oxidation1 2 3 4

14. Unsaturated Fatty Acid Oxidation1 2 3 4 1 2 3 4

15. Unsaturated Fatty Acid Oxidation1 2 4 3

16. Unsaturated Fatty Acid Oxidation

17. Unsaturated Fatty Acid Oxidation

18. 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

20. Fatty Acid Synthesis vs Oxidation

21. Fatty Acid Metabolism Located in Cytoplasm
Fatty Acid Synthesis - Regulation
Located in Cytoplasm
Feedback Inhibition by Long Chain Fatty Acids
Polymerization of Enzyme Favors Activation

22. 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

23. 3-Ketoacyl ACP Synthase
Fatty Acid Metabolism
Fatty Acid Synthesis
2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain
3-Ketoacyl ACP Synthase

24. 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
3-Ketoacyl ACP Reductase

25. 3-Hydroxyacyl ACP Dehydrase
Fatty Acid Metabolism
Fatty Acid Synthesis
4. Removal of Water, Creating a Trans Double Bond
3-Hydroxyacyl ACP Dehydrase

26. Fatty Acid Metabolism 5. Reduction of Double Bond
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

27. Fatty Acid Metabolism 6. Release of Palmitic Acid at End of Cycle
Fatty Acid Synthesis
6. Release of Palmitic Acid at End of Cycle
Palmitoyl-ACP
Palmitic Acid
ACP
Thioesterase

28. 1. Replacement of CoA with Acyl Carrier Protein (ACP)
Fatty Acid Metabolism
Fatty Acid Synthesis

29. 2. Joining of 2 Carbons from Malonyl-ACP to Growing Acyl Chain
Fatty Acid Metabolism
Fatty Acid Synthesis

30. Fatty Acid Metabolism 3. Reduction of Ketone on Beta Carbon
Fatty Acid Synthesis

31. 4. Removal of Water, Creating a Trans Double Bond
Fatty Acid Metabolism
Fatty Acid Synthesis

32. 5. Reduction of Double Bond
Fatty Acid Metabolism
Fatty Acid Synthesis

33. Fatty Acid Metabolism 6. Release of Palmitic Acid at End of Cycle
Fatty Acid Synthesis

34. Mammalian Desaturates Can’t Make Double Bonds Past Position Delta #9
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

36. Prostagen, Thromboxane, and Leukotriene Synthesis
Common Location of
Arachidonic Acid

37. Prostagen, Thromboxane, and Leukotriene Synthesis

38. Synthesis of Some Prostaglandins

41. Obesity
Females
Males

42. Obesity and Hunger Effects of leptin countered by ghrelin Leptin
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

43. The mouse on the left is deficient in leptin