Objectives

By the end of lecture the student should:

Discuss β oxidation of fatty acids. Illustrate α oxidation of fatty acids. Understand ω oxidation of fatty acids. List sources and fates of active acetate.

Oxidation of Fatty Acids 1- β-Oxidation (knoop’s oxidation): . Removal of 2 carbon fragment at a time form Acyl CoA (active FA). .The 2 carbon removed as acetyl CoA. .It occurs in many tissues including liver, kidney & heart FAs to be oxidized must be entered the following 2 steps

2- Transport of acyl 1-Activation of FA COA to mitochondria 1-FA activation

Acyl COA synthetase RCOOH RCO~SCOA

COASH ATP AMP+P~P

2Pi + E Pyrophosphatase 2- Transport of acyl COA to mitochondria:

. Role of carnitine in the transport of LCFA through the inner mithochochondrial membrane

Functions of carnitine

1- Transport long chain acyl COA across mitochondrial membrane into the mitochondria so it increases the rate of oxidation of LCFA

2- Transport acetyl-CoA from mitochondria to cytoplasm

So it stimulates fatty acid synthesis CoA CoA--SHSH H C α H3C3 α

β Cβ Palmitoyl Palmitoyl-CoA -CoA β O ~ S – CoA

α H3C α H3C β β CO CO ~ S~ –S CoA – CoA β + +

CH3 – CO ~ S –CoA Successive removal of C2 units Acetyl-CoA

8CH3 – CO ~ S – CoA 8CH3 – CO ~ S –Acetyl CoA-CoA Acetyl-CoA Steps of β- Oxidation of FAs

Energetics of FA oxidation Palmitic (16C): . β-oxidation of palmitic acid will be repeated 7 cycles producing 8 molecules of acetyl COA . In each cycle FADH2 and NADH+H+ is produced & transported to respiratory chain FADH2 ------ 2 ATP NADH+H+ ------ 3 ATP So 7 cycles 5X7=35 ATP . each acetyl-CoA which is oxidized in citric cycle gives 12 ATP (8X 12= 96 ATP) 2 ATP is utilized in the activation of fatty acid (it occurs once) Energy gain = Energy produced-Energy utilized = 35 ATP+ 96 ATP-2 ATP= 129 ATP Calculation of Energetics of any FA Oxidation: [(N/2-1)X 5 ATP]+[N/2X12 ATP]-2ATP (N= Number of carbons of fatty acid) 2- α – Oxidation

This type of oxidation occurs in α position with the removal of one carbon from the carboxyl end of fatty acids.  Site: microsomes of brain liver tissues

 Does not require coenzyme A & does not generate ATP. Mechanism

O2 H2O CH3 Hydroxylase CH3 OH

R.CH2 – CH – CH– COOH R.CH2 – CH – CH2 – COOH Even long chain FA α hydroxyl FA NADH+H+ NAD NAD

L ascorbic acid

NADH+H+ CO2 ½ O2 CH 3 CH3 O R.CH – CH – COOH β oxidation 2 R.CH2 – CH – C– COOH Odd long chain FA α Keto FA Functions: 1- Formation of α hydroxyl fatty acids which is a constituent of brain lipids 2- Modification of FA with methyl groups on the β carbon which block β oxidation e.g. phytanic acid present in certain plants, it has 4 CH3 groups at position 3, 7, 11, 15, by initial α oxidation & removal of one carbon, CH3 groups is at α position, FA undergo β oxidation

•rare neurological disorder

Refsum’s • caused by accumulation of phytanic disease acid, a constituent of chlorophyll found in plant foodstuffs • Phytanic acid contains a CH3 gp on C3 that block β oxidation. SO an initial α oxidation required to remove CH3 group •Pathology inherited defect in α oxidation leads to accumulation of phynatic acid 3- Omega Oxidation

• Occurs at terminal methyl group dicarboxylic acid (HOOC R COOH) • Site: microsomes of the liver

O2 H O Cyt P450 2 Cyt P450

CH3 – R – COOH OH – CH2 – R– COOH

NADH+H+ NADP

β oxidation

HOOC – CH2– COOH In both sides Dicarboxylic acid 3- Omega Oxidation

•The dicarboxylic acid formed may be shorted from both ends by β oxidation 2 molecules of acetyl COA each time • Oxidation continues usually to adipic (C6) & suberic (C6) acids which are excreted in urine Of active acetate (acetyl COA) 1- Carbohydrates: Glucose undergoes glycolysis forming pyruvic acid, which enters the mitochondria where it undergoes oxidation decarboxylation to form acetyl-CoA

2- Fats: Fats are hydrolysed into glycerol and FA

• Glycerol joins glycolysis at the step of dihydroxy acetone phospate pyruvic acid acetyl – CoA

• The fatty acid undergoes β – oxidation acetyl – CoA

3-Proteins:  Proteins are hydrolyzed to amino acids: • The ketogenic amino acids form acetyl- CoA directly or through the formation of aceto acetate • The glucogenic amino acids first form pyruvate either directly or through the formation of Kreb’s cycle intermediates Fate of acetyl CoA

1- Oxidation: Acetyl-CoA + oxalacetate citrate enter the Kreb’s cycle CO2 + water + 12 ATP

2- Formation of Fatty Acids (lipogenesis): The excess acetyl-CoA resulting from the oxidation of carbohydrates, or less commonly proteins, may be converted into fatty acids 3- Formation of Ketone Bodies: The excess acetyl-CoA resulting from oxidation of FA in the liver may form ketone bodies (ketogenesis)

4- Formation of Steroids: Acetyl-CoA cholesterol steroid hormones, bile acids & vitamin D3

5- Acetylation of Some Compunds: Acetyl-CoA is used for the acetylation of choline, glucosamine and aromatic amines Summary

Questions