Fatty Acid Metabolism - Oregon State...

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


α

β

α

β

• Similar to Malate Dehydrogenase Reaction of Citric Acid Cycle

Used to Generate ATP in Oxidative Phosphorylation


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


1 23 4


1 23 4

12 3 4


1 2 3 4

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


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

3-Ketoacyl ACP Synthase

3-Ketoacyl ACP Reductase


3. Reduction of Ketone on Beta Carbon

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


4. Removal of Water, Creating a Trans Double Bond

3-Hydroxyacyl ACP Dehydrase

Enoyl ACP Reductase


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


6. Release of Palmitic Acid at End of Cycle

Palmitoyl-ACP

Palmitic Acid

ACP

Thioesterase


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


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


3. Reduction of Ketone on Beta Carbon


4. Removal of Water, Creating a Trans Double Bond


5. Reduction of Double Bond


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

Fatty Acid Metabolism - Oregon State...

Documents

Transcript of Fatty Acid Metabolism - Oregon State...