Objectives By the end of lecture the student should:

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2 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.

3 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.

4 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

5 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

6 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

7 3- Omega Oxidation Occurs at terminal methyl group acid (HOOC R COOH) Site: microsomes of the liver dicarboxylic

8 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

9 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

10 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

11 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

12 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

13 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

14 Eicosaenoids The eicosaenoids are physiologically & pharmacologically active compounds derived from polyunsaturated fatty acid containing 20 carbon atoms (eicosaenoic acid) Physiologically they are considered to act as Local hormones functioning through G protein linked receptors to elicit their biochemical effects.

15 Eicosanoids prostanoids prostaglandins (PGs) Leukotrines (LTs) Lipoxins (LXs) prostacyclins (PGIs) thromboxanes (TXs)

16 Group 1 Eicosatrienoate 20:3 (8, 11, 14) Group 2 Eicosatetraenoate 20:4 (5, 8, 11, 14) Arachidonic Group 3 Eicosapentaenoate 20:5 (5, 8, 11, 14,17) PGE1 PGF1 PGI1 TXA1 LTA3 LTC3 LTD3 PGE2 PGF2 PGI2 TXA2 LTA4 LTC4 LTD4 LTE4 PGE3 PGF3 PGI3 TXI3 LTA5 LTC5 LTD5 Prostanoids Leukotrienes Prostanoids Leukotrienes Prostanoids Leukotrienes

17 The major classes of eicosanoids are given numbers according to the number of double bonds in the side chains of the molecule Because of a Cyclization reaction prostanoids have 2 fewer double bonds than the parent fatty acid while leukotrienes and lipoxins have the same number

18 Synthesis of eicosanoids Cyclooxygenase pathway Lipooxygenase pathway prostanoids LTs, LXs

23 Biological actions of eicosanoids 1-PGE2 2- F2α (PGE2α) 3-PGI2 4-TXA2 Relaxation of smooth muscle VD Induce labor Contraction of smooth Muscle VC Uterine contraction Produced by endothelium of Bl Vs VD inhibits platelets aggregation Produced by platelets VC Stimulates platelets aggregation

24 Excess production of prostaglandins results in a diverse group of symptoms, including pain, inflammation, fever, nausea, and vomiting The actions of thromoxane and prostacyclin are physiologically antagonistic

(TXA 2 ) Relaxes Coronary arteries Constricts The

25 Inhibits Platelet aggregation Stimulates Prostacyclin (PGI 2 ) Lowers Blood pressure Raises Thromboxane (TXA 2 ) Relaxes Coronary arteries Constricts The physiological antagonism between thromboxane and Prostacyclin

26 5- Leukotrienes: Leukotrienes were so named because they are synthesized in leukocytes and contain the typical triene structure, i.e. three double bonds in series. They are formed in leukocytes, platelets, and macrophages, they are involved in chemotaxis, inflammation, and allergic reactions.

27 1- Leukotriene D4 (LTD4) components of slowreacting substance of anaphylaxis (SRS-A), which causes: A- Smooth muscle contraction, & about 1000 times more potent than histamine in constricting the pulmonary airway (causing asthma) B- Increase fluid leakage from small vessels (causing swelling and oedema), & constricts coronary arteries. 2- Leukotriene B4 (LTB4) Attracts leukocytes (neutrophils and eosiophils), which are found in large number at sites of inflammation.

28 Glucocorticoids (cortisol) Synthesis of lipocortins & macrocortins -- phospholipase A2 activity Reduced inflammatory response -- PGs & LTS synthesis Unavailable archidonic A The anti-inflammatory effect of glucocorticoids hormones

29 The anti-inflammatory action of aspirin & NSAIDs Aspirin and NSAIDs, e.g. indomethacin and phenylbutazone inhibit the activity of cyclooxygenase, & therefore, prevent the synthesis of prostaglandins They do not affect synthesis of the leukotrienes Aspirin (acetylsalicylic acid) transfer an acetyl group to the enzyme, irreversibly inacting it. Other NSAIDs acts as reversible inhibitor of cyclooxygenase

30 The action of aspirin and glucocorticoids, indicate why steroids (e.g. cortisol), which inhibit total eicosanoids production, are better anti-inflammatory agent than aspirin like drugs, which only inhibit the cyclooxygenase pathway

31 The role of thromboxane on thrombus formation and myocardial infraction TXA2, a potent vasoconstrictor & stimulator of platelets aggregation, is the main eicosanoid in platelets. This action initiates thrombus formation at sites vascular injury & in the ruptured atherosclerotic plaque in the lumen of coronary arteries. The thrombi may cause sudden occlusion of vascular lumen causing acute ischemia (i.e. acute myocardial infarction)

32 The role of Aspirin in preventing acute myocardial infarction: Aspirin, by acetylating the active site of cyclooxygenase, blocks the production of TXA2 from its precursor, arachidonic acid. Low dose of aspirin is effective in prevention of acute myocardial infarction.

Fish & vascular heart diseases Diet that

33 Fish & vascular heart diseases Diet that include cold water fish (e.g. salmon, mackerel) contains high content of PUFAs of ω-3 series, eicosapentaenoic acid (EPA) results in a high content of these fatty acids in membrane phospholipids By action of cyclooxygenase, PGI3 & TXA3 produced on the expense of AA derived eicosanoids

than TXA 2 (produced from arachidonic acid).

34 Fish oil from diet Eicosapentaemoic acid (EPA) From cell membrane phospholipis Cyclooxygenase PGI 3 TXA 3 Produced by platelets less effective as aggregator than TXA 2 (produced from arachidonic acid). PGI 3 Produced by epithelium of blood vessels more potent as anti aggregator than PGI 2 (produced from arachidonic acid).

Such diets are effective in preventing heart diseases, because: 1- They lead to formation of more TXA3 & PGI3 relative to TXA2 & PGI2 TXA3 is less effective in stimulating platelets aggregation than

35 Such diets are effective in preventing heart diseases, because: 1- They lead to formation of more TXA3 & PGI3 relative to TXA2 & PGI2 TXA3 is less effective in stimulating platelets aggregation than TXA2. PGI3 is more potent as anti-aggregation of platelets than PGI2. Thus, the balance of activity is shifted toward non aggregation 2- decrease in the concentration of plasma cholesterol, triacyglycerol, LDL & VLDL 3- HDL is raised

36 Prostacyclin (PGI2) & atherosclerosis

Allowing blood platelets To aggregate on endothelial surface Lysosomal

37 Tissue & plasma lipid peroxides -- Prostacycilin synthetase Synthesis of PGI2 in arteries endothelium Development of atherosclerosis through Allowing blood platelets To aggregate on endothelial surface Lysosomal enz & toxic sub released from aggregated platelets leads to endoth injury

38 Summary

39 Questions

Objectives By the end of lecture the student should:

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.