Chemistry of Lipids 2.pdf

Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Chemistry of Lipids INTRODUCTION: Lipids are a major source of energy for the body besides their various other biochemical function and their role in cellular str...

Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Chemistry of Lipids INTRODUCTION: Lipids are a major source of energy for the body besides their various other biochemical function and their role in cellular structure. Lipids are a heterogenous group of water insoluble (hydrophobic) organic molecules. Lipids include fats, oils, steroids, waxes and related compounds. Definition of Lipids: Lipids are defined as esters of fatty acids with alcohol esters and are utilizable by the living organism. Classification of Lipids: There are many different methods of classifying lipids. The most commonly used classification of lipids is modified from Bloor as follows: 1. Simple lipids 2. Complex or compound lipids 3. Derived lipids. 4. Miscellaneous lipids. 1. Simple Lipids: These are esters of fatty acids with various alcohols. Depending on the type of alcohols, these are sub-classified as: a. Fats and oils (Neutral fats or triacylglycerol or triglycerides): These are esters of fatty acids with alcohol glycerol, e.g. tripalmitin. Because they are uncharged, they are termed as neutral fat. These are mono-, di-, and triacylglycerols, and cholesteryl esters. The fat we eat are mostly triglycerides. A fat in liquid state is called an oil, e.g. vegetable oils like groundnut oil, mustard oil, corn oil, etc. b. Waxes: Esters of fatty acids (usually long chain) with monohydric alcohols other than glycerol. These alcohols may be aliphatic or alicyclic. Cetyl alcohol is most commonly found in waxes. Waxes are widely used in pharmaceutical, cosmetic and other industries in the manufacture of candles, lotions, ointments and polishes. 2. Complex or Compound Lipids: These are esters of fatty acids, with alcohol containing additional (prosthetic) groups such as phosphate, nitrogenous base, carbohydrate, protein etc. They are further divided as follows: a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid and frequently a nitrogenous base. Phospholipids may be classified on the basis of the type of alcohol present in them as: i) Glycerophospholipids: The alcohol present is glycerol. Examples of glycerophospholipids are: Phosphatidyl choline (lecithin), Phosphatidyl ethenolamine (cephalin), Phosphatidyl serine, Phosphatidyl inositol, Plasmalogens, Cardiolipins. ii) Sphingophospholipids: The alcohol present is sphingosine. e.g., sphingomyelin. b. Glycolipids: Lipids containing fatty acid, alcohol sphingosine and additional residue are carbohydrates with nitrogen base. They do not contain phosphate group. These sugar containing sphingolipids are also called glycosphingolipids. For example: cerebrosides, gangliosides. c. Lipoproteins: Lipoproteins are formed by combination of lipid with a prosthetic group protein, e.g. serum lipoproteins like: Chylomicrons, Very low-density lipoprotein (VLDL), Low density lipoprotein (LDL), High density lipoprotein (HDL). d. Other complex lipids: Sulfolipids, aminolipids and lipopolysaccharides are among the other complex lipids. 3. Derived Lipids: Derived lipids include the products obtained after the hydrolysis of simple and compound lipids which possess the characteristics of lipids. These include glycerol and other alcohols, fatty acids, mono- and diacylglycerols, lipid (fat) soluble vitamins, cholesterol, and ketone bodies. 4. Miscellaneous lipids: These include a large number of compounds possessing the characteristics 1 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel of lipids e.g., carotenoids, squalene, hydrocarbons such as pentacosane (in bees wax), terpenes etc. Functions of Lipids: Lipids serve as: Storage form of energy: The fats and oils are used almost universally as stored forms of energy in living organisms. Structural Lipids: Lipids are major structural components of membranes, e.g. phospholipids, glycolipids and sterols. Cholesterol, a sterol, is a precursor of many steroid hormones, vitamin D and is also an important component of plasma membrane. Lipid acts as a thermal insulator in the subcutaneous tissues and around certain organs. Nonpolar lipids act as electrical insulators in neurons. Lipids are important dietary constituents because of the fat-soluble vitamins and essential fatty acids which are present in the fat of natural foods. Lipids help in absorption of fat-soluble vitamins (A, D, E and K). They act as a solvent for the transport of fat-soluble vitamins. They help in blood coagulation. Dipalmitoyl lecithin, a phospholipid act as surfactant and is required for the normal functioning of the lung alveoli. FATTY ACIDS: Definition: Fatty acids are aliphatic monocarboxylic organic acid with chain length usually ranging from C-4 to C-24 and it is a constituent of lipid. The fatty acids have the general formula R–CO–OH. Nomenclature of fatty acids: The naming of a fatty acid (systematic name) is based on the hydrocarbon from which it is derived. The saturated fatty acids end with a suffix -anoic (e.g., octanoic acid) while the unsaturated fatty acids end with a suffix -enoic (e.g., octadecenoic acid). In addition to systematic names, fatty acids have common names which are more widely used. Numbering of carbon atoms: It starts from the carboxyl carbon which is taken as number 1. The carbons adjacent to this (carboxyl C) are 2, 3, 4 and so on or alternately α, β, γ and so on. The terminal carbon containing methyl group is known omega (ω) carbon. Starting from the methyl end, the carbon atoms in a fatty acid are numbered as omega 1, 2, 3 etc. The numbering of carbon atoms in two different ways is given below Length of hydrocarbon chain of fatty acids: Depending on the length of carbon chains, fatty acids are categorized into 3 groups—short chain with less than 6 carbons; medium chain with 8 to 14 carbons and long chain with 16 to 24 carbons. Even and odd carbon fatty acids: Most of the fatty acids that occur in natural lipids are of even carbons (usually 14C – 20C). This is due to the fact that biosynthesis of fatty acids mainly occurs with the sequential addition of 2 carbon units. Palmitic acid (16C) and stearic acid (18C) are the most common. Among the odd chain fatty acids, e.g. valeric acid (5C). Shorthand representation of fatty acids: Instead of writing the full structures, biochemists employ shorthand notations (by numbers) to represent fatty acids. The general rule is that the total number 2 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel of carbon atoms are written first, followed by the number of double bonds and finally the (first carbon) position of double bonds, starting from the carboxyl end. Thus, saturated fatty acid, palmitic acid is written as 16 : 0, oleic acid as 18 : 1; 9 or Δ9, 18:1, arachidonic acid as 20 : 4; 5, 8, 11, 14 or 20:4, Δ5, 8, 11,14. There are other conventions of representing the double bonds. 9 indicates that the double bond is between 9 and 10 of the fatty acid. ω 9 represents the double bond position (9 and 10) from the ω end. Naturally occurring unsaturated fatty acids belong to ω 9, ω 6 and ω 3 series. ω 3 series Linolenic acid (18 : 3; 9, 12, 15) ω 6 series Linoleic acid (18 : 2; 9, 12) and arachidonic acid (20 : 4; 5, 8, 11, 14) ω 9 series Oleic acid (18 : 1; 9) Linolenic acid is ω-3 series The linoleic acid is called ω-6 series because of the presence of first double bond from ω-6 carbon at the 6th carbon Arachidonic acid is ω-6 series Classification of Fatty Acid: Saturated Fatty Acid: No double bond presents. For example: Butyric acid (4 carbon atoms), Palmitic acid (C16), Stearic acid (C18), Lignoceric acid (C24). Unsaturated Fatty Acids: Contain one or more double bonds. They are further classified into—monounsaturated fatty acid [MUFA]: Contains one double bond, e.g. palmitoleic acid (C16, Δ9), oleic acid (C18, Δ9) Polyunsaturated fatty acid: Contains more than one double bond [PUFA]. For example: Linoleic acid (C18, Δ9,12), Linolenic acid (C18, Δ9, 12, 15), Arachidonic acid (C20, Δ5, 8, 11,14). ESSENTIAL FATTY ACIDS: Fatty acids, that are required for optimal health and cannot be synthesized by the body and should be supplied in the diet are called essential fatty acids. They are polyunsaturated fatty acids, namely linoleic acid and linolenic acid. Arachidonic acid can be synthesized from linoleic acid. Therefore, in deficiency of linoleic acid, arachidonic acid also becomes essential fatty acids. These fatty acids are not synthesized in the human body because of lack of the desaturase enzyme, which introduces double bonds beyond 9th and 10th carbon atoms. Hence, humans cannot synthesize linoleic acid and linolenic acid having double bonds beyond C9. And thus, linoleic and linolenic are the essential fatty acids. Functions of Essential Fatty Acids (EFA): 1) Synthesis of Eicosanoids: Linoleic acid and linolenic acid supplied by the diet are the precursors for the synthesis of a variety of other unsaturated fatty acids. Arachidonic acid, a fatty acid derived from linoleic acid is an essential precursor of eicosanoids (They act as local hormones), which include: 3 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Prostaglandins Thromboxanes Prostacyclin Leukotrienes. 2) Maintenance of Structural Integrity: EFAs are required for membrane structure and function. These fatty acids are important constituents of phospholipids in cell membrane and membranes of cell organelle (e.g. mitochondria) and help to maintain the structural integrity of the membrane. 3) Development of Retina and Brain: Docosahexaenoic acid (DHA: ω-3), which is synthesized from linolenic acid is particularly needed for development of the brain and retina during the neonatal period. 4) Antiatherogenic Effect: Essential fatty acids increase esterification and excretion of cholesterol, thereby lowering the serum cholesterol level. Thus, essential fatty acids help to prevent the atherosclerosis. 5) Prevention of fatty liver. 6) Formation of lipoproteins. Essential Fatty Acid Deficiency: Deficiency of EFAs is characterized by scaly skin, eczema (in children), loss of hair and poor wound healing. Impaired lipid transport and fatty liver may occur due to deficiency of EFAs. EFAs deficiency decreases efficiency of biological oxidation. Cis vs Trans Fatty Acid: Cis: Both H atoms are on the same side of the C=C double bond, which causes a bend in their structure Cis isomers are less stable than trans isomers. Most of the naturally occurring unsaturated fatty acids exist as cis isomers. Trans: Both H atoms are on opposite sides of the C=C double bond. – Do not bend and have physical properties similar to saturated fatty acids – Are not commonly found in nature. Major sources of trans—fatty acids: Margarine, Cakes and cookies, Snack chips, Meat and dairy products, Peanut butter, Fried foods. Hydroxy fatty acids: Some of the fatty acids are hydroxylated. β-Hydroxybutyric acid, one of the ketone bodies produced in metabolism, is a simple example of hydroxy fatty acids. Cerebronic acid and recinoleic acid are long chain hydroxy fatty acids. Cyclic fatty acids: Fatty acids with cyclic structures are rather rare e.g., chaulmoogric acid found in chaulmoogra oil (used in leprosy treatment) contains cyclopentenyl ring. 4 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel TRIACYLGLYCEROLS OR TRIACYLGLYCERIDES OR NEUTRAL FAT: These are esters of fatty acids with glycerol. Triacylglycerol consists of three fatty acids, which are esterified through their carboxyl groups, resulting in a loss of negative charge and formation of neutral fat. (Figure 1). Triacylglycerols containing the same kind of fatty acid in all three positions are called simple triacylglycerols. Mixed triacylglycerols contain two or more different fatty acids. The fatty acid on carbon 1 is usually saturated. That on carbon 2 is usually unsaturated and that on carbon 3 can be either of the two. The stereospecific numbering (sn) of the glycerol carbon atom is shown in Figure 1. As the polar hydroxyl groups of glycerol and polar carboxyl groups of the fatty acids are bound in ester linkages, triacylglycerols are nonpolar, hydrophobic and neutral (in charges) molecules, essentially insoluble in water. The presence of the unsaturated fatty acid(s) in triacylglycerol decreases the melting temperature of the lipid and remains in liquid form (oil). Vegetable oils such as corn and olive oil are composed largely of triacylglycerols with unsaturated fatty acids and thus are liquids at room temperature. Triacylglycerols containing only saturated fatty acids, such as beef fat, are white greasy solids at room temperature. Fats as stored fuel: Triacylglycerols are the most abundant group of lipids that primarily function as fuel reserves of animals. The fat reserve of normal humans (men 20%, women 25% by weight) is sufficient to meet the body’s caloric requirements for 2-3 months. Figure 1: Glycerol and triacylglycerol PHOSPHOLIPIDS: These are made up of fatty acid, glycerol or other alcohol, phosphoric acid and nitrogenous base. Phospholipids are the major lipid constituents of cell membranes. Like fatty acids, phospholipids are amphipathic in nature, i.e. each has a hydrophilic or polar head (phosphate group) and a long hydrophobic tail (containing two fatty acid chains). Classification of Phospholipids: There are two classes of phospholipids (Figure 2): 1. Glycerophospholipids or phosphoglycerides, that contain glycerol as the alcohol. 2. Sphingophospholipids that contain sphingosine as the alcohol. Glycerophospholipids or Phosphoglycerides: Glycerophospholipids are the major lipids that occur in biological membranes. They consist of glycerol 3-phosphate esterified at its C1 and C2 with fatty acids. Usually, C1 contains a saturated fatty acid while C2 contains an unsaturated fatty acid. The C3 5 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel hydroxyl group of the glycerol is esterified to phosphoric acid and resulting compound called, phosphatidic acid (Figure 3). Phosphatidic acid is a key intermediate in the biosynthesis of other glycerophospholipids. Figure 2: Classification of phospholipids Figure 3 a: Diagrammatic representation of amphipathic Phospholipid Figure 3 b: Structure of glycerol and phosphatidic acid In glycerophospholipid, phosphate group of phosphatidic acid becomes esterified with the hydroxyl group of one of the several nitrogen base or other groups. Different types of glycerophospholipids are discussed below: 6 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Phosphatidylcholine (lecithin): These are glycerophospholipids containing choline (Figure 4). These are most abundant phospholipids of the cell membrane having both structural and metabolic functions. Dipalmitoyl lecithin is an important phosphatidylcholine found in lungs, secreted by pulmonary type II epithelial cell. It acts as a lung surfactant and is necessary for normal lung function. It is a surface- active agent and prevents the adherence of inner surface of the lungs due to surface tension. Respiratory distress syndrome in infants is a disorder characterized by the absence of dipalmitoyl lecithin. The lungs of immature infants do not have enough type II epithelial cells to synthesize sufficient amounts of dipalmitoyl phosphatidylcholine (DPPC). In its absence, the lungs tend to collapse and this condition is known as respiratory distress syndrome. Phosphatidylethanolanine (Cephalin): They differ from lecithin in having nitrogenous base ethanolamine in place of choline (Figure 4). Thromboplastin (coagulation factor III), which is needed to initiate the clotting process, is composed mainly of cephalins. Phosphatidylserine: It contains the amino acid serine rather than ethanolamine and is found in most tissues (Figure 4). Phosphatidylinositol: In phosphatidylinositol, inositol is present as the stereoisomer myoinositol (Figure 4). This is an important component of cell membranes. Phosphatidylinositol is a second messenger for the action of hormones like oxytocin and vasopressin. Plasmalogens: Plasmalogens are generally similar to other phospholipids but the fatty acid at C1 of glycerol is linked through an ether, rather than an ester bond (Figure 4). There are three major classes of plasmalogens: Phosphatidalcholines, Phosphatidalethanolamines, Phosphatidalserines. These are found in myelin and in cardiac muscle. Plasmalogen is a platelet activating factor (PAF) and involved in platelet aggregation and degranulation. Lysophospholipids: Lysophospholipids are formed by removal of the fatty acid either at C1 or C2 of glycerophospholipid. The most common of these are lysophosphatidylcholine (lysolecithin) (Fig. 4) and lysophosphatidylethanolamine. Cardiolipin (Diphosphatidylglycerol): It is so named as it was first isolated from heart muscle. Structurally, a cardiolipin consists of two molecules of phosphatidic acid held by an additional glycerol through phosphate groups. It is an important component of inner mitochondrial membrane and essential for mitochondrial function for optimum function of the electron transport process. Decreased cardiolipin levels may result in mitochondrial dysfunction, aging, hypothyroidism, cardioskeletal myopathy (Barth syndrome). Cardiolipin is the only human phosphoglyceride that possesses antigenic properties. Sphingophospholipids: Phospholipids derived from alcohol sphingosine (amino alcohol) instead of glycerol are called sphingophospholipids, e.g. sphingomyelin. 7 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Figure 4: Structure of different phospholipids Sphingomyelin: Sphingomyelin is the only phospholipid in membranes that is not derived from glycerol. Instead, the alcohol in sphingomyelin is sphingosine. 8 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel In sphingomyelin, the amino group of the sphingosine is linked to a fatty acid to yield ceramide (sphingosine fatty acid complex). In addition, the primary hydroxy group of sphingosine is esterified with phosphorylcholine (Fig. 4). Sphingomyelins are important constituents of myelin and are found in good quantity in brain and nervous tissues. Ceramide, acts as a second messenger (signaling molecule) by regulating programmed cell death (apoptosis), cell cycle and cell differentiation. A ceramide containing a 30-carbon fatty acid is a major component of skin, and it regulates skin’s water permeability. Functions of Phospholipids: 1) Phospholipids are the major lipid constituents of cell membranes. In association with proteins, phospholipids form the structural components of membranes and regulate membrane permeability. 2) They regulate permeability of membranes as well as activation of some membrane bound enzymes. 3) Arachidonic acid, an unsaturated fatty acid liberated from phospholipids, serves as a precursor for the synthesis of eicosanoids (prostaglandins, prostacyclins, thromboxanes etc.). 4) Phospholipids are of importance in insulating the nerve impulse (like the plastic or rubber covering around an electric wire) from the surrounding structures, e.g. sphingomyelins act as electrical insulators in the myelin sheath around nerve fibers. 5) Phospholipids are important constituents of lipoproteins. Therefore, phospholipids participate in the reverse cholesterol transport and thus help in the removal of cholesterol from the body. 6) Phospholipids are essential for the synthesis of different lipoproteins, and thus participate in the transport of lipids. 7) Phospholipids act as a lipotropic factor. Lipotropic factor is the component that prevents fatty liver, i.e. accumulation of fat in the liver. 8) These are good emulsifying agents that help in intestinal absorption of lipids. 9) Thromboplastin (coagulation factor III), which is needed to initiate the clotting process, is composed mainly of cephalins. 10) Phospholipid (lecithin) acts as lung surfactant, which prevents alveolar collapse. 11) Lecithin represents a storage form of lipotropic factor choline. 12) Phosphatidylinositol is the source of second messengers—inositol triphosphate and diacylglycerol, that are involved in the action of some hormones. 13) In mitochondria, cardiolipin is necessary for optimum functions of the electron transport process. 14) Plasmalogens (platelet activating factor) involved in platelet aggregation and degranulation. GLYCOLIPIDS (GLYCOSPHINGOLIPIDS): Glycolipids as their name implies, are sugar containing lipids. Glycolipids consist of alcohol sphingosine. Glycolipids (glycosphingolipids) are widely distributed in every tissue of the body, particularly in nervous tissue (particularly the brain). Classification of Glycolipids: Four classes of glycolipids have been distinguished: 1. Cerebrosides 2. Sulfatides 3. Globosides 4. Gangliosides. Cerebrosides (Ceramide + Monosaccharides): Cerebroside is the simplest glycolipid in which there is only one sugar residue, either glucose or galactose linked to ceramide and named as glucocerebroside and galactocerebroside respectively. Galactocerebroside is found in nerve tissue membrane, whereas glucocerebroside is the predominant 9 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel glycolipid of extra neural (non-neural) tissues, where it acts as a precursor for the synthesis of more complex glycolipids, e.g. gangliosides. Sulfatides (Ceramide + Monosaccharide + Sulfate): Sulfatides are cerebrosides in which the monosaccharide contains a sulfate ester. Globosides (Ceramide + Oligosaccharide): Globosides contain two or more sugar molecules attached to ceramide. These glycolipids are important constituents of the RBC-membrane and are the determinants of the A, B, O blood group system Gangliosides (Cerebroside + Oligosaccharides + N-acetylneuraminic acid, NANA): These are predominantly found in ganglions and are the most complex form of glycosphingolipids. Gangliosides are the derivatives of cerebrosides and contain one or more molecules of N- acetylneuraminic acid (NANA), the most important sialic acid. Several types of gangliosides such as GM1, GM2, GM3, etc. have been isolated from brain and other tissues. The most important gangliosides present in the brain are GM1, GM2, GD, and GT, (G represents ganglioside while M, D and T indicate mono-, di- or tri- sialic acid residues, and the number denotes the carbohydrate sequence attached to the ceramide). The ganglioside, GM2 that accumulates in Tay- Sachs disease. The simplest ganglioside found in tissues is GM3. M represents mono which indicate presence of one residue of NANA and subscript number assigned on the basis of chromatographic migration of ganglioside. 10 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel GM1 is a more complex ganglioside derived from GM3. Functions of Glycolipids: Glycolipids are important constituents of the nervous tissue, such as brain and outer leaflet of all cell membrane. They play a role in the regulation of cellular interactions, growth and development. Glycolipids serve as cell surface receptors for certain hormones and a number of drugs. They also serve as receptors for cholera and tetanus toxins. Glycolipids are antigenic and they have been identified as a source of blood group antigens. CHOLESTEROL (ANIMAL STEROL): Cholesterol is the major sterol in animal tissues. Sterols (means solid alcohol) are a class of steroids containing one or more hydroxyl groups. It consists of steroid nucleus namely cyclopentanoperhydrophenanthrene (CPPP) containing 19 carbon atoms (Figure 5). It consists of a phenanthrene nucleus (rings A, B and C) to which a cyclopentane ring (D) is attached. It consists of methyl side chains at position C10 and C13 which are shown as single bonds. Cholesterol, a 27-carbon compound, has an 8-carbon side chain attached to the D ring at C17 and a hydroxyl group attached to C3 of the A ring, with one double bond between carbon atoms 5 and 6 (Figure 6). Cholesterol is weakly amphipathic, with a polar head the hydroxyl group at C3 and a nonpolar, the steroid nucleus and hydrocarbon side chain at C17. Most of the cholesterol in the body exists as a cholesterol ester, with a fatty acid attached to the hydroxyl group at C3. Cholesterol is widely distributed in all the cells of the body but particularly in nervous tissue, and is a major component of cell membranes and lipoproteins. Normal fasting serum cholesterol level is 150 to 200 mg/dL. Excess cholesterol is harmful to body in that it gets deposited in the intima of the arteries producing atherosclerosis. This can narrow the lumen of blood vessel impeding blood flow, which cause 11 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel thrombosis. Cholesterol occurs in animal fats but not in the plant fats. Figure 5: The steroid nucleus, phenanthrene (ring A, B and C), to which cyclopentane D ring is attached Figure 6: The structure of cholesterol Functions of Cholesterol: Cholesterol is a poor conductor of heat and electricity, since it has a high dielectric constant. It is present in abundance in nervous tissues. It appears that cholesterol functions as an insulating cover for the transmission of electrical impulses in the nervous tissue. Cholesterol performs several other biochemical functions which include its role in membrane structure and function. Cholesterol serves as the precursor for a variety of biologically important products, including: 1. Steroid hormones: Cholesterol is the precursor of the five steroid hormones, e.g. i. Progesterones ii. Glucocorticoids iii. Mineralocorticoids iv. Androgens (male sex hormones). v. Estrogen (female sex hormones). 2. Bile acids: Bile acids, derived from cholesterol, act as a detergent in the intestine, emulsifying dietary fats to make them readily accessible to digestive enzyme lipase. 3. Vitamin D: It is derived from cholesterol and is essential in calcium and phosphate metabolism. Cardiovascular Disease: Deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in familial hypercholesterolemia is the development of coronary artery disease (atherosclerosis) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest pain) or heart attacks. EICOSANOIDS: Prostaglandins and the related compounds thromboxanes and leukotriens, are collectively known as eicosanoids. Eicosanoids are synthesized from arachidonic acid. Prostaglandins: Prostaglandins are derivatives of a hypothetical 20 carbon fatty acid namely prostanoic acid (Fig.7). They derive their name from the tissue in which they were first recognized (the prostate gland) but they are now known to be present in almost all tissues. 12 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Figure 7: The structure of arachidonic acid, prostanoic acid, common prostaglandin (PGE2), thromboxane (TXA2) and leukotrienes (LTA4) Prostaglandins are named as PG plus a third letter (E, F, A, D), which corresponds to the type, and arrangement of functional group in the molecule and the subscript indicate number of double bonds [PGE1]. Prostaglandins are synthesized from arachidonic acid, which is released from membrane bound phospholipids. Corticosteroid and aspirin inhibit the prostaglandin synthesis. They act as local hormones and are involved in a wide range of biochemical function. In general prostaglandins are involved in the lowering of blood pressure, induction of inflammation, medical termination of pregnancy, induction of labor, inhibition of gastric HCl secretion, decrease in immune response and increase in glomerular filtration rate. Sixteen naturally occurring prostaglandins have been described but only seven are found commonly throughout the body. These are PGE1, PGE2, PGF1α, PGF2α, PGG2, PGH2, PGI2. Prostaglandins are not stored, instead the precursor C20 arachidonic acids are stored in tissues. Synthesis: Arachidonic acid is the precursor for most of the prostaglandins in humans. Release of arachidonic acid from membrane bound phospholipids by phospholipase A 2− this is due to the stimuli by epinephrine or bradykinin. Oxidation and cyclization of Arachidonic acid to PGG2, which is then converted to PGH2 by a reduced 13 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel glutathione dependent peroxidase. PGH2 serves as the immediate precursor for the synthesis of a number of prostaglandins, including prostacyclins and thromboxanes (Fig. 8). Figure 8: Prostaglandin synthesis Inhibition of PG Synthesis: A number of structurally unrelated compounds can inhibit prostaglandin synthesis. Cortisol inhibit the enzyme phospholipase A 2. Aspirin irreversibly inhibits the cyclooxygenase. Functions of prostaglandins: Prostaglandins and other eicosanoids have hormone like actions. Prostaglandins in many tissues act by regulating the synthesis of cyclic AMP (cAMP). As cAMP mediates the action of many hormones, the prostaglandins affect a wide range of cellular and tissue functions. Some of these are: −Smooth muscle contraction and relaxation: For example, in pregnancy PGF2α are produced in response to oxytocin and act to promote uterine contraction. Because of this effect, they have been used to terminate unwanted pregnancies. PGE2 are involved in relaxation of bronchial smooth muscle. −Inflammatory response: The PGs (PGE1 and PGE2) induce the symptoms of inflammation (redness, swelling, edema, etc.) due to arteriolar vasodilation. Corticosteroids are usually used to treat inflammation which inhibits PG synthesis. −Platelet aggregation: Prostaglandins have an effect on platelet aggregation. PGE 2 promote aggregation and are thus, involved in the blood clotting. −Regulation of Blood pressure: PGE2 decrease blood pressure. It can lower systemic arterial pressure through their vasodilator effect. −Body temperature: Prostaglandins elevate body temperature producing fever and cause inflammation, resulting in pain. −Gastric secretion: PGE2 suppress gastric secretion. −PGs are involved in Na+ and water retention by kidney tubules. Thromboxanes: Thromboxanes were first isolated from blood platelets, thrombocytes— hence the name. They have six membered oxane ring (Figure 9) that includes an oxygen atom. 14 Chemistry of Lipids Biochemistry Dr. Saeed Mohammed Ismaeel Nomenclature of thromboxanes: Thromboxanes are abbreviated as TX. Different capital letters are used to designate different substituents of the ring (like prostaglandins). A subscript, if present, denotes the number of unsaturated bonds (double bonds), e.g. the most common thromboxane TXA2 having two double bonds. Functions of thromboxanes: TXA2 is produced by platelets, promotes platelets aggregation. Platelet aggregation initiates thrombus formation at sites of vascular injury. TXA2 causes contractions of the smooth muscles of the arterial wall and therefore, raises blood pressure. Leukotrienes (LT): Leukotrienes were so named because they were initially described in leucocytes and are characterized by a conjugated triene system but no such ring structure that is found in prostaglandins and thromboxanes. Nomenclature of leukotrienes: All leukotrienes are abbreviated as LT. These are grouped into five classes (A to E) based on the type of substituents attached to the parent compound. The LTs found in humans have a subscript four to denote that they contain four double bonds (Fig.9). Functions of leukotrienes: The LTs facilitate chemotaxis, inflammation and allergic reactions. LTC4, LTD4 induce contraction of muscle of the lung and constrict pulmonary airways. Overproduction of LT causes asthmatic attacks. LTD4 has been identified as the slow reacting substance of anaphylaxis (SRS-A) which causes smooth muscle contraction. LTB4 attracts neutrophils and eosinophils to sites of inflammation. Certain fish foods contain an unsaturated fatty acid namely eicosapentanoic acid (EPA) (20 carbon atoms and 5 double bonds), which inhibit the synthesis of thromboxanes (TXA 2), thus decrease platelet aggregation and thrombosis and therefore lower the risk of myocardial complications as seen in the Eskimos. 15