Introduction to lipidsIntroduction to lipidsIntroduction to lipidsIntroduction to lipidsIntroduction to lipids

introduction to lipids

1. Chemistry of Lipids Department of Biomedical Sciences

2. Definition of Lipids Lipids (Greek, ‘ lipos ’-fat) are heterogeneous groups of compounds, including fats, oils, steroids, waxes, and others which are related more by their physical than by their chemical properties. They have a common property of being: (a) relatively insoluble in water due to lack of polarizing atoms (b) soluble in non polar solvents such as ether and chloroform. Fourth major group of molecules found in the cell. Lipids are not polymeric (unlike nucleic acids, proteins & polysaccharides). Q1: Define Lipids? 2

3. Bloor’s Criteria According to Bloor , lipids are compounds having the following characteristics: They are insoluble in water. Solubility in one or more organic solvents, such as ether, chloroform, benzene, acetone, etc., so called fat solvents. Some relationship to the fatty acids as esters either actual or potential. Possibility of utilization by living organisms. 3

4. Functions/biological importance of lipids They are important dietary constituents because of : Their high energy value than carbohydrates and proteins (why they have high energy value?) Supply essential fatty acids that cannot be synthesized by the body. Supply the body with fat-soluble vitamins (A, D, E and K). Fats also increase the bioavailability of compounds known as phytochemicals, which are plant constituents such as lycopene (found in tomatoes) and beta-carotene (found in carrots). 4

5. Functions … Sensory properties in food (texture, taste, smell and satiety of food) that contribute to mouth-watering aromas and flavors. 2 . Fat is stored in adipose tissue Glycogen is quite bulky with heavy water content, thus the body cannot store too much for long. Alternatively, fats are packed together tightly without water and store far greater amounts of energy in a reduced space. Can be stored in the body in almost unlimited amount in contrast to carbohydrates. 5

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7. Functions… Unlike other body cells that can store fat in limited supplies, fat cells are specialized for fat storage and are able to expand almost indefinitely in size. it serves as a mechanical and thermal insulator. Visceral fat surrounds/cushioning vital organs such as the heart, kidneys, and liver. Subcutaneous fat, or fat underneath the skin, insulates the body from extreme temperatures and helps keep the internal climate under control. 7

8. Functions… 3. Non-polar lipids act as electrical insulators , allowing rapid propagation of waves along myelinated nerves. Nerve response in myelinated neurons propagate faster than in unmyelinated neurons. Myelin is a mixture of proteins and phospholipids that insulates nerves. The myelin coating is ~70% lipids . 4. Lipoprotéines are important constituent of cell membrane and mitochondria, and means of transporting lipids in the blood. 5. As cell surface components concerned in cell recognition, species specificity and tissue immunity 8

9. Functions…. 6. As activators of enzymes – for example, phosphatidylcholine micelles for activation of microsomal enzymes. 7. Intense biological activity – some have profound biological activity; they include some of the vitamins and hormones 8. Lipoproteins and phospholipids are important constituents of many natural membranes such as cell walls and cell organelles like mitochondrion, etc 8. Knowledge of lipid biochemistry is necessary in understanding many important biomedical areas, eg , obesity, diabetes mellitus, atherosclerosis, and the role of various polyunsaturated fatty acids in nutrition and health. Q2: Describe the biomedical functions of lipids? 9

10. General properties Although the properties vary from one class to other, some of the general properties of lipids are: Soluble in non-polar solvents but only sparingly soluble in water. Greasy or fat-like in nature and show translucent properties Most lipids are amphipathic (Greek, amphi , double) i.e., one end of a lipid molecule, the head, is polar or ionic and therefore, hydrophilic; the other end, the tail (hydrocarbon) is non-polar and therefore hydrophobic. Most lipids contain fatty acids. The acylgycerols esters of un-saturated fatty acids are usually liquids at room temperature and Fats and oils containing unsaturated fatty acids slowly become rancid when exposed to light, heat, moisture and air. Q3: What is rancidity? 10

11. Classification of Lipids I. Simple lipids : Esters of fatty acids with various alcohols. Fats: Esters of fatty acids with glycerol(solid). Oils : fats in the liquid state. Waxes: are esters of fatty acids with higher monohydroxy aliphatic alcohols True waxes: are esters of higher fatty acids with acetyl alcohol ( C 16 H 33 OH ) or other higher straight chain monohydroxy alcohols (waxes are resistant to oxidation ). Cholesterol esters Vitamin A and Vitamin D esters Q4: Differentiate fats/oils from waxes in terms of structure? 11

12. Glycerol reacts with 3 fatty acids (Esterification reaction) Fats/Oils ( Triacylglycerols) 12 Example of Simple Lipids: The triacylglycerols/TAG

13. II. Complex lipids /Compound Lipids Esters of fatty acids containing groups in addition to an alcohol and a fatty acid. Phospholipids:- Esters of the above type containing phosphoric acid residue. a) Glycerophospholipid:- The alcohol is glycerol b) Sphingophospholipids:- The alcohol is shingosine. Glycolipids :- Lipids containing carbohydrate moiety are called glycolipids. They contain a special alcohol called sphingosine or sphingol and nitrogenous base in addition to fatty acids but does not contain phosphoric acid or glycerol . Q5 : Which complex lipids are cell-surface antigenic determinants? 13

14. Others:- Include sulfolipids , amino-lipids ( proteolipids ) and lipoproteins, which are modified forms of lipids. III. Precursor and derived lipids Derivatives obtained by hydrolysis of those given in group I and II, which still possess the general characteristics of lipids. These include:- a. Fatty acids b. Alcohols (Cholesterol, Glycerol, Vitamin D, Retinol and certain carotenoids), steroids c. ketone bodies d. Monoglycerides and diglycerides Note : Triacylglycerols (Triglycerides), cholesterol, and cholesteryl - esters are termed neutral lipids, because they are uncharged. 14

15. Example of Complex lipids: Phospholipids Structure of Phospholipids Phospholipid bilayer of Cell membrane 15

16. Derived Lipids A. Fatty acids Definition: A fatty acid (FA) may be defined as an organic acid that occurs in a natural triglycerides (fats and oils), but do occur in the un -esterified form as free fatty acids, a transport form found in the plasma carried by albumin and is a monocarboxylic acid ranging in chain length from C4 to about 24 carbon atoms. FA are obtained from hydrolysis of triglycerides. The chain may be saturated ( containing no double bonds) or unsaturated ( containing one or more double bonds ). Mostly the double bond occurs at the 9 th carbon counting from the carboxyl group end. 16

17. Fatty acids… Fatty acids that occur in natural fats are usually straight-chain derivatives containing an even number of carbon atoms, (2,4, 6, etc, carbon atoms). Odd chain fatty acids have 3, 5, 7, etc carbon atoms, are seen in microbial cell walls and in milk. Depending on the length of the hydrocarbon chain, there are short chain fatty acids with 2 to 6 carbon atoms, medium chain fatty acids, with 8 to 14 carbon atoms and long chain fatty acids with 16 or more carbon atoms up to 24 carbon atoms. 17

18. Nomenclature of Fatty acids The most frequently used systematic nomenclature names the fatty acid after the hydrocarbon with the same number and arrangement of carbon atoms, with – anoic or enoic being added as suffix being substituted for the final -e ( Genevan system) . Thus, saturated fatty acids end in - anoic , eg , octanoic acid, and unsaturated fatty acids with double bonds end in - enoic , eg , octadecenoic acid (oleic acid). Carbon atoms are numbered from the carboxyl carbon (carbon No. 1). 18

19. Nomenclature… The carbon atoms adjacent to the carboxyl carbon (Nos. 2, 3, and 4) are also known as the α, β, and γ carbons, respectively, and the terminal methyl carbon is known as the ω or n-carbon . Various conventions use Δ for indicating the number and position of the double bonds, e.g. Δ 9 indicates a double bond between carbons 9 and 10 of the fatty acid; ω9 or n-9 indicates a double bond on the ninth carbon counting from the ω- carbon. 19

20. Nomenclature… A widely used convention is to express the fatty acids by formula to indicate: The number of carbon atoms The number of double bonds and The positions of the double bonds Q6 : Describe the conventions used to indicate the number & position double bond in fatty acids? 20

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22. Physical state of fatty acids The melting point of a fatty acid increases with chain length and decreases with the degree of unsaturation. Thus, fatty acids with many double bonds, such as those in vegetable oils, are liquid at room temperature and saturated fatty acids, such as those in butterfat, are solids. Lipids with lower melting points are more fluid at body temperature and contribute to the fluidity of our cellular membranes In practice, natural acylglycerols contain a mixture of fatty acids tailored to suit their functional roles. 22

23. Saturated and Unsaturated fatty acids Saturated fatty acids have single bonds between the carbons in the chain, and unsaturated fatty acids contain one or more double bonds. The most common saturated fatty acids present in the cell are palmitic acid (C16) and stearic acid (C18). Monunsaturated fatty acids contain one double bond, and polyunsaturated fatty acids contain two or more double bonds. The kinks made by double bonded C in unsaturated fatty acids prevent the molecules from packing tightly together. 23

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26. Saturated fatty acids Vs Unsaturated fatty acids 26 Unsaturated fatty acids have kinks in their tails. The kinks in the unsaturated side chains prevent close packing of the hydrocarbon portions of the phospholipids.

27. 27 Saturated fatty acids Vs Unsaturated fatty acids…

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29. Geometric Isomers in Unsaturated fatty acids Most naturally occurring unsaturated fatty acids have cis - double bonds A type of geometric isomerism occurs in unsaturated fatty acids, depending on the orientation of atoms or groups around the axes of double bonds, which do not allow rotation. If the acyl chains are on the same side of the double bond, it is cis -, as in oleic acid; if on opposite sides , it is trans-, as in elaidic acid, the trans isomer of oleic acid . Increase in the number of cis double bonds in a fatty acid leads to a variety of possible spatial configurations of the molecule— e.g., arachidonic acid, with four cis -double bonds, has “kinks” or a U shape. 29

30. Geometric Isomers in Unsaturated fatty acids… This has profound significance on molecular packing in membranes and on the positions occupied by fatty acids in more complex molecules such as phospholipids. T rans-double bonds alter these spatial relationships. Trans fatty acids are present in certain foods, arising as a by-product of the saturation of fatty acids during hydrogenation, or “hardening,” of natural oils in the manufacture of margarine, and they seriously affect health. Q8: Mention the example of the trans isomers of fatty acids & describe the health effect of these isomers. 30

31. Geometric Isomers in Unsaturated fatty acids… 31 Trans fatty acids Naturally present in small amounts (<1% of total calories) in animal food sources, including human milk Mainly introduced in the food chain by the industrial process of hydrogenation „ This process is used to make oils solid at room temperature or “partially hydrogenated oils."

32. Nutritionally essential fatty acids Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them.  The term "essential fatty acid" refers to fatty acids required for biological processes but does not include the fats that only act as fuel. Only two fatty acids are known to be essential for humans:  alpha- linolenic acid (an omega-3 fatty acid) and  Linoleic acid (an omega-6 fatty acid). 32

33. Why EFA cannot be Synthesised ? 33

34. Why EFA cannot be Synthesised ?... 34 Routes of synthesis of other fatty acids (See De novo fatty acids biosynthesis). Palmitate is the precursor of stearate and longer-chain saturated fatty acids, as well as the monounsaturated acids palmitoleate and oleate . Mammals cannot convert oleate to linoleate or α - linolenate (shaded pink), which are therefore required in the diet as essential fatty acids.

35. Functions of EFA(Biomedical Importance) Structural elements of tissues: Polyunsaturated fatty acids occur in higher concentration in lipids associated with structural elements of tissues. Proper development and functioning of the brain and nervous system . Synthesis of prostaglandins and other compounds: Thromboxanes Leukotrienes Prostaglandins Structural element of gonads: Lipids of gonads also contain a high concentration of polyunsaturated fatty acids, which suggests importance of these compounds in reproductive function . 35

36. Functions of EFA… Structural element of mitochondrial membrane: A deficiency of EFA causes swelling of mitochondrial membrane and reduction in efficiency of oxidative phosphorylation . This may explain for increased heat production noted in EFA deficient animals. Serum level of cholesterol: Fats with high content of polyunsaturated fatty acids tends to lower serum level of cholesterol. Effect on clotting time: Prolongation of clotting time is noted in ingestion of fats rich in EFA. 36

37. Functions of EFA… Effect on fibrinolytic activity: An increase in fibrinolytic activity follows the ingestion of fats rich in EFA. Role of EFA in fatty liver: Deficiency of EFA produces fatty liver. Role in vision: Docosahexaenoic acid (22:6n-3) is the most abundant polyenoic fatty acids present in retinal photoreceptor membranes. Docosahexaenoic acid is formed from dietary linolenic acid. It enhances the electrical response of the photoreceptors to illumination. Hence linolenic acid is necessary in the diet for optimal vision. 37

38. B. Alcohols: Glycerol and steroids Glycerol Glycerol is commonly called as “glycerin ”. it is the simplest trihydric alcohol as it contains three hydroxyl groups in the molecule It is colorless oily fluid with a sweetish taste. It is miscible with water and alcohol in all proportions but is almost insoluble in ether 38

39. Sources of Glycerol Industrial It is obtained as a by-product of soap manufacturing It is also obtainable by the fermentation of glucose Physiological Endogenous source: Main source is from lipolysis of fats in adipose tissue. Exogenous source: Dietary Approx. 22 per cent of glycerol directly absorbed to portal blood from the gut. 39

40. Uses of Glycerol Industrial : Glycerol finds many uses in industry, as a result of its solubility, its solvent action and its hygroscopic nature. Many pharmaceuticals and cosmetic preparations have glycerol in their formulas. In medicine: Nitroglycerine is used as a vasodilator. Glycerol therapy in cerebrovascular (CV) diseases reduces cerebral edema . Physiological: In body, glycerol has a definite nutritive value . It can be converted to glucose/and glycogen, the process called as gluconeogenesis. 40

41. 2. Steroids The steroids ( stereos G = solid) are one of the most studied classes of biological compounds and are often found in association with fat. Since they contain no fatty acids, they are nonsaponifiable Steroids contain a four-ring fused structure called the steroid nucleus cyclopentanoperhydrophenanthrene . This system consists of 3 cyclohexane rings (A, B and C) fused in nonlinear or phenanthrene manner and a terminal cyclopentane ring (D). Steroids are complex fat-soluble molecules, which are present in the plasma lipoproteins and outer cell membrane. 41

42. Steroids… Cholesterol is probably the best known steroid because of its association with atherosclerosis. However, biochemically it is also of significance because it is the precursor of a large number of equally important steroids that include the bile acids, adrenocortical hormones, sex hormones, D vitamins, cardiac glycosides, phytosterols of the plant kingdom, and some alkaloids. Cholesterol is the steroid precursor in human cells from which all of the steroid hormones are synthesized by modifications to the ring or C20 side chain. 42

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44. Steroids… Although cholesterol is not very water soluble, it is converted to amphipathic water-soluble bile salts such as cholic acid . Bile salts line the surfaces of lipid droplets called micelles in the lumen of the intestine, where they keep the droplets emulsified in the aqueous environment. Cholesterol is one of the compounds synthesized in the human from branched 5- carbon units with one double bond called an isoprenyl unit (2- methyl-1,3-butadiene), a methyl-branched compound with five C atoms. 44

45. Steroids… Activated acetic acid as a component of lipids Although the lipids found in plant and animal organisms occur in many different forms, they are all closely related biogenetically; they are all derived from acetyl-CoA, the “activated acetic acid”. 1. One major pathway leads from acetyl-CoA to the activated fatty acids ( acyl-CoA) . Fats, phospholipids, and glycolipids are synthesized from these, and fatty acid derivatives in particular are formed. 45

46. Steroids… 2. The second pathway leads from acetyl- CoA to isopentenyl diphosphate ( “active isoprene”), the basic component of the isoprenoids . Activated isoprene, isopentenyl diphosphate , is used by plants and animals to biosynthesize linear and cyclic oligomers and polymers. Isoprenyl Units are combined in long chains to form other structures, such as the side chains of coenzyme Q in humans and vitamin A in plants. Its biosynthesis is discussed in connection with biosynthesis of the isoprenoid , cholesterol. 46

47. Steroids… 47 Steroids are polyprenyl (isoprene-based) molecules built on a core structure of three 6-membered rings and one 5-membered ring, all fused together.

48. Functions of cholesterol For the synthesis of bile salts that are important in lipid digestion and absorption. For the synthesis of steroid hormones that are biologically important like the sex hormones estrogen and progesterone & hormones of adrenal cortex. For the synthesis of vitamin D3. As a structural material in biological membranes. As a component of lipoproteins as transport forms of lipid based energy. 48

49. Properties of cholesterol It has a hydroxyl group on C3, a double bond between C5 and C6, 8 asymmetric carbon atoms and a side chain of 8 carbon atoms. It is found in all animal cells, corpus luteum and adrenal cortex, human brain (17% of the solids). In the blood (the total cholesterol amounts about 200 mg/ dL of which 2/3 is esterified , chiefly to unsaturated fatty acids while the remainder occurs as the free cholesterol. 49

50. Properties of cholesterol… Intestinal bacteria reduce cholesterol into coprosterol and dihydrocholesterol . It is also oxidized into 7-Dehydrocholesterol and further unsaturated cholesterol with a second double bond between C7 and C8. When the skin is irradiated with ultraviolet light 7-dehydrocholesterol is converted to vitamin D3. 50

51. Simple Lipids: Triacylglycerols (triglycerides)=TAG Are the main storage forms of fatty acids The triacylglycerols , are esters of the trihydric alcohol glycerol and 3 fatty acids. Mono- and diacylglycerols wherein, one or two fatty acids are esterified with glycerol, respectively, are also found in the tissues. These are of particular significance in the synthesis and hydrolysis of triacylglycerols . An acylglycerol comprises glycerol with one or more fatty acids (the acyl group) attached through ester linkages. 51

52. Triacylglycerols … To number the carbon atoms of glycerol unambiguously, the - sn - (stereo-chemical numbering) system is used. In the three-dimensional configuration of glycerol, carbons 1 and 3 are not identical (shown as a projection formula in the following figure) and even enzymes are specific for one or the other carbon. E.g . glycerol is always phosphorylated on sn-3 by glycerol kinase to give glycerol -3-phosphate and not glycerol-1-phosphate. 52

53. Triacylglycerols… Tri acylglycerols rarely contain the same fatty acid at all three positions and are therefore called mixed triacylglycerols . Triacylglycerol containing the same fatty acids are called simple triacylglycerols Unsaturated fatty acids, when present, are most often esterified to carbon 2. 53

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55. Triacylglycerols … The fatty acid on carbon 1 is typically saturated, that on carbon 2 is typically unsaturated, and that on carbon 3 can be either. The presence of the unsaturated fatty acid(s) decrease(s) the melting temperature (Tm) of the lipid. 55

56. Fig. Fatty acid composition of three food fats. The melting point of these fats & hence the physical state at room T O is direct function of their fatty acid composition. 56

57. Triacylglycerols … Since TAGs are only slightly soluble in water and cannot form stable micelles by themselves, they coalesce within adipocytes to form oily droplets that are nearly anhydrous/entirely free of water. These cytosolic lipid droplets are the major energy reserve of the body. 57

58. Properties TAG Specific gravity : It is lower than that of water Greasy or fat like and show translucent properties Solubility: All triglycerides are insoluble in water and do not tend by themselves to form highly dispersed micelles. They are soluble in non-polar solvents. Melting point: It is determined by their fatty acid composition. In general, the melting point increases with the increasing carbon chain length of the saturated fatty acid components whereas it decreases with increase in degree of unsaturation. 58

59. Properties TAG… Optical activity: Although glycerol itself is optically inactive, carbon atom 2 becomes asymmetric whenever the fatty acid substituents on carbon atoms 1 and 3 are different. Auto-oxidation: Fats and oils rich in unsaturated fatty acids slowly oxidize when exposed to atmospheric oxygen, light, heat and moisture and develop off-flavor and off-odor. Prevention of rancidity: Vegetable fats contain certain substances like vitamin E, phenols, hydroquinones , tannins and others which are antioxidants and prevents development of rancidity. Hence vegetable fats preserve for longer periods than animal fats. 59

60. Properties TAG… Hydrolysis: All triglycerides on hydrolysis yield three molecules of fatty acids and one molecule of glycerol when boiled with acids or bases or by the action of enzymes called lipases. Saponification : Hydrolysis of triglycerides or fats and oils by alkali is called saponification . The free fatty acids formed by the hydrolysis of triglycerides react with excess of alkali to form metallic salts called soaps. Sodium and potassium slats of fatty acids are soluble in water (soft soaps ). Oxidation : Many fats and oil when stored for long time they often become rancid-develop off-flavor and off-odor. 60

61. Properties TAG… Hydrogenation: Hydrogen can be made to combine with unsaturated fats and oils to produce hydrogenated shortening. This reaction is used to enhance the keeping quality of vegetable oils used for food. The reaction of hydrogen with fats and oils is used commercially to produce hydrogenated shortening and margarine . Emulsification: Emulsions of fat may be made by shaking vigorously in water and by emulsifying agents such as gums, bile salts, soaps and proteins which produce more stable emulsions. 61

62. Functions of Triacylglycerols Energy source 9 kcal per gram Form of stored energy in adipose tissue Insulation and protection Carrier of fat-soluble vitamins Sensory properties in food 62

63. Compound Lipids Phospholipids There are two classes of phospholipids: those that have glycerol (from glucose) as a backbone and those that have sphingosine (from serine and palmitate ). Phospholipids a re amphipathic molecules They are of 2 types Glycerophospholipids Sphingophospholipids 63

64. A- Glycerophospholipids They are regarded as derivatives of phosphatidic acids and include: Phosphatidic acids Lecithins Cephalins Plasmalogens Inositides Cardiolipin 64

65. Glycerophospholipids… The most abundant lipids in cell membranes. Composed of glycerol, two fatty acids, phosphate, and an amino alcohol. Have both polar and non polar regions that allow them to interact with polar and non polar substances. Have a polar head containing the ionized amino alcohol and phosphate portion, which are strongly attracted to water. Have a hydrocarbon tail portion only soluble in non polar substances. These lipids just play an important role in cellular permeability 65

66. 1. Phosphatidic acid/ phosphotidyl / Phosphatidate It is the simplest phosphoacylglycerol ( phosphoglyceride ). Phosphatidic acid is composed of diacylglycerol with a phosphate group on the third carbon. It is precursor of the other glycerophospholipids . Phosphatidic acid is important as an intermediate in the synthesis of triacylglycerols /TAG/fat as well as phosphoacylglycerols but is not found in any great quantity in tissues. 66

67. General structure of glycerophospholipids (Phosphatidic acid & its derivatives) 67

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69. 2. Phosphotidylcholine ( Lecithins ) Named from Likithos in Greek = Yolk Phosphoacylglycerols containing choline as a base or amino alcohol are the most abundant phospholipids of the cell membrane and represent a large proportion of the body’s store of choline . Choline is important for synthesis acetylcholine , and as a store of labile methyl groups. Are a common cell constituent of the brain, egg yolk, or liver. Are important in the metabolism of fat by the liver & their absence leads to fatty liver. 69

70. 70 The structure of phosphatidylcholine The Biosynthesis of Phosphatidylcholine

71. Lecithins ... 71 Dipalmitoyl lecithin is a very effective surface active agent and a major constituent of the surfactant preventing adherence, due to surface tension, of the inner surfaces of the lungs. Its absence from the lungs of premature infants causes respiratory distress syndrome Besides its used for activating macrophages to kill pathogens.

72. Lysophospholipids / lysolecithin These are phosphoacylglycerols containing only one acyl radical eg , lysophosphatidylcholine ( lysolecithin ), important in the metabolism and inter-conversion of phospholipids It is also found in oxidized lipoproteins and has been implicated in some of their effects in promoting atherosclerosis. 72

73. 3.Phosphatidylethanolamine ( cephalin ) Cephalins occur in association with lecithins in tissues and were intially isolated from the brain ( Kephale = head) Structure: Cephalins resemble lecithins in structure except that choline is replaced by ethanolamine or serine. Certain cephalins are constituents of the complex mixture of phospholipids, cholesterol and The lipoprotein in blood “ thromboplastin ” which accelerates the clotting of blood by activation of Prothrombine to thrombin in presence of calcium ions contains cephalin . 73

74. Cephalin… 74

75. 4. Cardiolipin / diphosphatidylglycerol Two molecules of Phosphatadic acids esterified through their phosphate groups to an additional molecule of glycerol is called cardiolipin , initially isolated from heart muscle (cardio). In eukaryotes, cardiolipin is virtually exclusive to the inner mitochondrial membrane , where it appears to be required for the maintenance of certain respiratory complexes of the electron transport chain. Decreased cardiolipin levels or alterations in its structure or metabolism cause mitochondrial dysfunction in aging, is accounted for heart failure, hypothyroidism and some types of myopathies. 75

76. Cardiolipin… Cardiolipin is also abundantly present in the cell membranes of bacteria . Cardiolipin is antigenic, and is recognized by antibodies raised against Treponema pallidum, the bacterium that causes syphilis. Used in serological diagnosis of autoimmunity diseases. 76 Structure of cardiolipin

77. 5. Plasmalogens / phosphoglyceralacetals These compounds constitute as much as 10% of the phospholipids of brain and muscle. It is an ether lipid. Structurally, the plasmalogens resemble phosphatidylethanolamine but have an aliphatic long chain unsaturated alcohol in ether linkage to with the first hydroxyl group of glycerol. In some instances, choline, serine, or inositol may be substituted for ethanolamine. Myelin contains large amount of ethanolamine plasmalogen , and heart muscles contains large amounts of choline plasmalogen. 77

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79. Structure: They are similar to lecithins or cephalins but they have the cyclic sugar alcohol, inositol as the base. They are formed of glycerol, one saturated fatty acid, one unsaturated fatty acid, phosphoric acid and inositol . Phosphatidyl inositol is a major component of cell membrane phospholipids particularly at the inner leaflet of it. 79 6 . Phosphoinositides ( Phosphatidyl inositols ) or inositides

80. Phosphoinositides/ Inositides/… They play a major role as second messengers during signal transduction for certain hormone. On hydrolysis by phospholipase C, phosphatidyl-inositol-4,5-diphosphate produces diacyl -glycerol and inositol-triphosphate . Both act to liberate calcium from its intracellular stores to mediate the hormone effects. 80

81. Inositides as secondary messenger 81

82. Role of inositides in membrane protein anchoring Specific proteins can be covalently attached via a carbohydrate bridge to membrane bound inositides Examples of such proteins include alkaline phosphatase (a digestive enzyme found on the surface of the small intestine that attacks organic phosphates), and acetyl choline esterase (an enzyme of the postsynaptic membrane that degrades the neuro transmitter acetylcholine). 82

83. Degradation of phosphoacylglycerols The degradation of phosphoglycerides is performed by phospho lipases found in all tissues and pancreatic juice. A number of toxins and venoms have phospholipase activity, and several pathogenic bacteria produce phospholipases that dissolve cell membranes and allow the spread of infection. Phospholipases hydrolyze the ester or phosphodiester bonds of phosphoglycerides , with each enzyme cleaving the phospholipid at a specific site. 83

84. Degradation of phosphoacylglycerols … Removal of the fatty acid from carbon 1 or 2 of a phosphoglyceride produces a lysophospho glyceride, which is the substrate for lysophospholipases . Phospho lipases release molecules that can serve as messengers (for example, DAG and IP3), or that are the substrates for synthesis of messengers (for example, arachidonic acid). 84

85. Degradation of phosphoacylglycerols … Phospho lipases are responsible not only for degrading phospholipids, but also for “remodeling” them. For example, phospholipases A1 and A2 remove specific fatty acids from membrane-bound phospholipids; these can be replaced with alternative fatty acids using fatty acyl CoA transferase . 85

86. Fig. Specificities of phospholipases 86

87. Specificities Phospholipases Phospholipase A 1 specifically removes the fatty acid from the 1 position and phospholipase A 2 from the 2 position. Phospholipase B (a mixture of phospholipase A 1 and A 2 ) catlayzes successive removal of the two fatty acids of phosphoglycerides . Phospholipase C hydrolyzes the bond between phosphoric acid and glycerol. while phospholipase D removes the polar head group to leave a phosphatidic acid. 87

88. B- Sphingolipids Are second largest membrane lipids, which contain two non-polar and one polar head groups. Their alcohol is the amino alcohol sphingosine , derived from serine and a specific fatty acid, palmitate . Sphingolipids have two classes: Sphingomyelins / Phosphosphingosides / Glycolipids Cerebrosides Sulfatides Gangliosides Ceramides are the precursors of both phosphorylated and glycosylated sphingolipids . 88

89. General structure of sphingolipids 89 Sphingosine

90. 90 Fig. General structure of sphingolipids

91. 1. Sphingomyelins Sphingomyelins are found in large amounts in brain and nerves(hence their name, sphingomyelins ) and apparently lack in plants and the microorganisms. On hydrolysis, the sphingomyelins yield a fatty acid, phosphoric acid, choline, and a complex amino alcohol ( sphingosine ). They contain two nitrogenous bases: sphingosine itself and choline . To the amino group of sphingosine and fatty acid is attached by an amide linkage = forms ceramide 91

92. The structure of Sphingomyelin 92

93. Sphingomyelins cont… Sphingomyelins are differ from lecithins in that they contain sphingosine as the alcohol instead of glycerol . they contain one fatty acid Sphingomyelin is an important constituent of the myelin of nerve fibers , membranous structure that insulates and protects neuronal fibers of the central nervous system. 93

94. Degradation of sphingomyelin Sphingomyelin is degraded by sphingomyelinase , a lysosomal enzyme that hydrolytically removes phosphorylcholine , leaving a ceramide . The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free fatty acid. 94

95. Niemann–Pick disease (=sphingomyelin lipidosis) Is a rare genetic disorder, inherited as an autosomal recessive condition. The disease is caused by a deficiency of the enzyme sphingomyelinase , which cleaves ceramide - phosphocholine bond of sphingomyelin . As a result, sphingomyelin accumulates in large amounts in the reticuloendothelial system since their synthesis is normal in rate but their degradation is interrupted. Niemann –Pick cells (prototype of ‘foam cells’) are found in the bone marrow, spleen, lymphoid tissues, liver, lung and tissues, of virtually any organ. 95

96. Niemann Pick Disease… 96

97. Types of Niemann-Pick disease Clinically, the disease manifests itself in two forms : (a) Early or infantile form (type A). This is characterized by hepatosplenomegaly , macular degeneration, cherry-red retinal spot (=macula) in nearly half of the cases, mental retardation and blindness. Death ensues by two years of age. (b) Late or adult form (type B). This perhaps is the most common of the two forms and reveals intellectual impairment during late infancy, slow evolution of the disease, no changes in the ocular fundi and survival beyond the age of five. However, death of the patient occurs by the second decade. 97

98. 2. Glycolipids Glycolipids are derivatives of ceramides in which a long-chain fatty acid is attached to the amino alcohol sphingosine , more precisely called glycosphingolipids . Glycolipids are molecules that contain both carbohydrate and lipid components. Glycosphingolipids are essential components of the outer leaflet of the plasma membrane , but they are found in greatest amounts in nerve tissue . As such, they play a role in the regulation of cellular interactions , growth, and development. 98

99. Glycolipids… Glycosphingolipids are antigenic, and they have been identified as a source of blood group antigens. The carbohydrate portion of a glycolipid is the antigenic determinant (remember sugar code). They elicit production of antibodies when cells (e.g., during blood transfusion) or tissues (e.g., during tissue and organ transplantation) are transferred from one individual to another. 99

100. Glycolipids… They also serve as cell surface receptors for cholera and tetanus toxins , as well as for certain viruses (like influenza viruse) and microbes. Genetic disorders associated with an inability to properly degrade the glycosphingolipids result in lysosomal accumulation of these compounds. 100

101. Classification of glycolipids According to the number and nature of the carbohydrate residue(s) present in the glycolipids , they are classified as a. Cerebrosides . They are present in cerebral tissue , therefore are called cerebrosides . They contain either a molecule of galactose ( galactocerebroside ) or glucose ( glucocerebroside ). b. Sulfatides . They are cerebrosides with sulfate on the sugar (sulfated cerebrosides ). c . Gangliosides . They have several sugar and sugar amine residues. 101

102. a. Cerebrosides/ Neutral glycosphingolipids These are ceramide monosaccharides that contain either a molecule of galactose ( galactocerebroside ) or glucose ( glucocerebroside ). As their name implies, cerebrosides are found predominantly in the brain and peripheral nervous tissue. 102

103. Acidic Glycosphingolipids 103 Acidic glycosphingolipids are negatively charged at physiologic pH. The negative charge is provided by N- acetylneuraminic acid (NANA, a sialic acid, in gangliosides , or by sulfate groups in sulfatides / sulfolipids /.

104. b. Sulfatides/Sulfoglycosphingolipids Sulfatides are cerebrosides that contain sulfated galactosyl residues, and are therefore negatively charged at physiologic pH. Sulfatides are found predominantly in the brain and kidneys. 104

105. c. Gangliosides These are found primarily in the ganglion cells of the central nervous system, particularly at the nerve endings. They are derivatives of ceramide oligosaccharides, and contain one or more molecules of NANA. The notation for these compounds is G (for ganglioside ), plus a subscript M, D, T, or Q to indicate whether there is one (mono), two (di), three (tri), or four ( quatro ) molecules of NANA in the ganglioside , respectively. The subscript number assigned are on the basis of chromatographic migration. Gangliosides are of medical interest because several lipid storage disorders involve the accumulation of NANA-containing glycosphingolipids in cells. 105

106. 106 Note: Globosides ( Ceramide oligosaccharides) :They contain two or more hexoses or hexosamines , attached to a ceramide molecule.

107. 107 Summary of sphingolipids

108. 108 Glycosphingolipids as determinants of blood groups

109. 109

110. Glycospingolipidosis Disorder Deficient Enzyme Accumulating compound Symptoms Gaucher disease Glucosidase / Glucocerebrosidase Glucocerebrosides Hepatosplenomegally , Mental retardation, Bone degeneration Fabry Disease Galactosidase Galactocerebrosides Kidney failure, Skin rashes Tay -Sachs Disease Gangiolosidase G M2 gangliosides Rapidly progressing mental retardation 110

111. Orientation of amphipathic lipids in aqueous environment Lipids f orm Membranes, Micelles, Liposomes, & Emulsions in aqueous solutions In general, lipids are insoluble in water since they contain a predominance of non-polar (hydrocarbon) groups. However, fatty acids, phospholipids, sphingolipids , bile salts, and, to a lesser extent, cholesterol contain polar groups. Therefore, part of the molecule is hydrophobic, or water-insoluble; and part is hydrophilic, or water-soluble. Such molecules are described as amphipathic 111

112. Amphipathic lipids orientation They become oriented at oil: water interfaces with the polar group in the water phase and the non-polar group in the oil phase. A bilayer of such amphipathic lipids has been regarded as a basic structure in biologic membranes. 112

113. Why are there so many membrane lipids? they act as permeability barriers for cells and organelles; they provide the matrix for assembly and function of a wide variety of catalytic processes; they directly participate in metabolism, e.g. as donors for the synthesis of molecules or as substrates for desaturation they participate in a multitude of membrane fusion events; they actively influence the functional properties of membrane-associated processes. 113

114. Amphipathic lipids orientation… When a critical concentration of these lipids is present in an aqueous medium, they form micelles. Aggregations of bile salts into micelles and the formation of mixed micelles with the products of fat digestion are important in facilitating absorption of lipids from the intestine. 114

115. Emulsions Emulsions are much larger particles, formed usually by non-polar lipids in an aqueous medium. These are stabilized by emulsifying agents such as amphipathic lipids ( eg , lecithin), which form a surface layer separating the main bulk of the non-polar material from the aqueous phase. 115

116. Liposomes Liposomes may be formed by sonicating an amphipathic lipid in an aqueous medium. They consist of spheres of lipid bilayers that enclose part of the aqueous medium. 116

117. Liposomes… Liposomes are of potential clinical use—particularly when combined with tissue specific antibodies—as carriers of drugs in the circulation, targeted to specific organs, eg , in cancer therapy. Certainly some success has been achieved by encapsulation of anticancer drugs (e.g . vincristine) when the toxic side-effects of the therapy seem to be reduced . 117

118. Liposomes… In addition, as carriers for topical and trans-dermal delivery of drugs and cosmetics . An interesting commercial application of liposomes has been the development of skin preparations. These types of moisturizing creams are lotions that are claimed to remove wrinkle-lines and are anti-ageing. Liposomes have more recently been used as a vehicle for DNA transfection. Ultimately this technique can be used for gene therapy. The method has been termed ‘ lipofection ’ 118

119. 119

120. Lipoproteins/transport form of lipids/ Lipoproteins are water-soluble complexes of lipids, phospholipids and proteins that are used to transport lipids through the blood Lipoproteins are soluble in water because their surface is polar - the polar head groups of phospholipids and the hydroxyl groups of cholesterol form a polar layer on the surface of the lipoprotein - non-polar triacylglycerides and cholesterol esters (cholesterol in the blood is mostly fatty acid esters) are stored in the interior 120

121. General structure of lipoproteins 121

122. 122 Size and Composition of Plasma lipoproteins