Objectives By the end of lecture the student should:

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Denis French
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2 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.

3 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

4 FAs to be oxidized must be entered the following 2 steps 1-Activation of FA 2- Transport of acyl COA to mitochondria

5 1-FA activation RCOOH Acyl COA synthetase RCO~SCOA COASH ATP AMP+P~P 2Pi + E Pyrophosphatase

6 2- Transport of acyl COA to mitochondria: Role of carnitine in the transport of LCFA through the inner mithochochondrial membrane

8 1- Transport long chain acyl COA across mitochondrial membrane into the mitochondria so it increases the rate of oxidation of LCFA Functions of carnitine 2- Transport acetyl-coa from mitochondria to cytoplasm So it stimulates fatty acid synthesis

9 H 3 C H 3 C α α CoA-SH CoA-SH Palmitoyl-CoA Palmitoyl-CoA β β Cβ O ~ S CoA H 3 C H 3 C α α β β β CO CO ~ S ~ S CoA CoA CH 3 CO ~ S CoA Successive removal of C2 units Acetyl-CoA + + 8CH 3 CO ~ S CoA Acetyl-CoA 8CH 3 CO ~ S CoA Acetyl-CoA

10 Steps of β- Oxidation of FAs

12 Palmitic (16C): Energetics of FA oxidation 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 FADH ATP NADH+H 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

13 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)

14 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.

15 Mechanism CH 3 R.CH 2 CH CH 2 COOH Even long chain FA O 2 H 2 O Hydroxylase NADH+H + NAD CH 3 OH R.CH 2 CH CH COOH α hydroxyl FA NAD L ascorbic acid β oxidation CH 3 R.CH 2 CH COOH Odd long chain FA CO 2 ½ O 2 NADH+H + CH 3 O R.CH 2 CH C COOH α Keto FA

16 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

Refsum s disease rare neurological disorder caused by accumulation of phytanic acid, a constituent of chlorophyll found in plant foodstuffs Phytanic acid contains a CH3

17 Refsum s disease rare neurological disorder caused by accumulation of phytanic 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

18 3- Omega Oxidation Occurs at terminal methyl group acid (HOOC R COOH) Site: microsomes of the liver dicarboxylic

19 O 2 Cyt P450 H 2O Cyt P450 CH 3 R COOH OH CH 2 R COOH NADH+H + NADP β oxidation In both sides HOOC CH 2 COOH Dicarboxylic acid

20 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

21 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

22 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

23 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:

24 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

25 Summary

26 Questions

Objectives By the end of lecture the student should:

Objectives By the end of lecture the student should: Illustrate α oxidation of fatty acids. Understand ω oxidation of fatty acids. List sources and fates of active acetate. Discuss eicosanoids. 2- α Oxidation