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  1. 1. Introduction  Definition: water insoluble compounds  Most lipids are fatty acids or ester of fatty acid  They are soluble in non-polar solvents such as petroleum ether, benzene, chloroform  Functions     Energy storage Structure of cell membranes Thermal blanket and cushion Precursors of hormones (steroids and prostaglandins)  Types:  Fatty acids  Neutral lipids  Phospholipids and other lipids
  2. 2. Classification: Saponifiable—can be hydrolyzed by NaOH to make soap Non-saponifiable—cannot be hydrolyzed, includes sterols such as cholesterol Saponifiable lipids are further subdivided: Simple- made of fatty acids plus alcohol Compound- either phospho- or glyco- lipids, which contain phosphate or sugar groups as well as fatty acids
  3. 3. Lipids are non-polar (hydrophobic) compounds, soluble in organic solvents. Most membrane lipids are amphipathic, having a non-polar end and a polar end. Fatty acids consist of a hydrocarbon chain with a carboxylic acid at one end. - A 16-C fatty acid: CH3(CH2)14 COO Non-polar - polar A 16-C fatty acid with one cis double bond between represented as 16:1 cis ∆ 9. C atoms 9-10 may be
  4. 4. Double bonds in fatty acids usually have the cis configuration. Most naturally occurring fatty acids have an even number of carbon atoms. γ 4 β 3 α 2 O C 1 O− fatty acid with a cis-∆9 double bond Some fatty acids and their common names: 14:0 myristic acid; 16:0 palmitic acid; 18:0 stearic acid; 18:1 cis∆9 oleic acid 18:2 cis∆9,12 linoleic acid 18:3 cis∆9,12,15 α-linonenic acid 20:4 cis∆5,8,11,14 arachidonic acid 20:5 cis∆5,8,11,14,17 eicosapentaenoic acid (an omega-3)
  5. 5. γ 4 β 3 α 2 O C 1 O− fatty acid with a cis-∆9 double bond There is free rotation about C-C bonds in the fatty acid hydrocarbon, except where there is a double bond. Each cis double bond causes a kink in the chain. Rotation about other C-C bonds would permit a more linear structure than shown, but there would be a kink.
  6. 6. Fats & Oils Simplest lipids, called triacylglycerols or simply triglycerides. Main form of fat storage in plants, animals, and man. Males store 21% fat on average, females 26%.
  7. 7. Essential Fatty Acids Fatty acids which cannot be made by the body, but are important for health and growth are called essential. Linolenic acid, found mostly in vegetable oils, is an important reducer of LDL (low density lipoproteins), which help to take cholesterol into the blood and cause atherosclerosis (buildup of plaque in the blood vessels) a prime cause of heart attacks Arachidonic acid is important in making eicosanoids, molecules which regulate and protect the body from invasion by microorganisms.
  8. 8. Simple Lipids—Fatty Acids Simple triglycerides contain the same fatty acid in all three positions; mixed triglycerides contain two or three different fatty acids Fatty acids are carboxylic acids with from 4 to 20 carbons in the chain. The chain can be saturated (only single bonds) or unsaturated (one or more double bonds in the chain), Saturated are usually solid at room temperature, unsaturated are usually liquid
  9. 9. Less common fatty acids H3 C  iso – isobutyric acid  anteiso R H3 C R H3C CH3  odd carbon fatty acid – propionic acid  hydroxy fatty acids – ricinoleic acid, dihydroxystearic acid, cerebronic acid  cyclic fatty acids – hydnocarpic, chaulmoogric (CH2)12-CO2H (CH2)10-CO2H acid chaulmoogric acid hydnocarpic acid
  10. 10. H3C COOH CH3 CH3 CH3 CH3 PHYTANIC ACID A plant derived fatty acid with 16 carbons and branches at C 3, C7, C11 and C15. Present in dairy products and ruminant fats. A peroxisome responsible for the metabolism of phytanic acid is defective in some individuals. This leads to a disease called Refsum’s disease Refsum’s disease is characterized by peripheral polyneuropathy, cerebellar ataxia and retinitis pigmentosa
  11. 11. Less common fatty acids H3C (CH2)10 C C (CH2)4 COOH TARIRIC ACID H2C CH (CH2)4 C C C C (CH2)7 COOH ERYTHROGENIC ACID These are alkyne fatty acids
  12. 12. Unsaturated fatty acids  number and position of the double bond(s)Various conventions are in use for indicating the 18 H3C (CH2)7 H C 1 9 CH(CH2)7COOH 10 9 18:1,9 or ∆ 18:1 ω H3C n 2 3 4 5 6 7 8 9 10 CH2CH2CH2CH2CH2CH2CH2CH 17 ω 9, C18:1 or n-9, 18:1 18 CH(CH2)7COOH 10 9 1
  13. 13. Unsaturated fatty acids  Monoenoic acids (one double bond):  16:1, 9 ω7: palmitoleic acid (cis-9-hexadecenoic acid  18:1, 9 ω9: oleic acid (cis-9-octadecenoic acid)  18:1, 9 ω9: elaidic acid (trans-9-octadecenoic acid)  22:1, 13 ω9: erucic acid (cis-13-docosenoic acid)  24:1, 15 ω9: nervonic acid (cis-15-tetracosenoic acid)
  14. 14. Unsaturated fatty acids  Trienoic acids (3 double bonds)  18:3;6,9,12 ω6 : γ-linolenic acid (all cis-6,9,12octadecatrienoic acid)  18:3; 9,12,15 ω3 : α-linolenic acid (all-cis-9,12,15octadecatrienoic acid)  Tetraenoic acids (4 double bonds)  20:4; 5,8,11,14 ω6: arachidonic acid (all-cis-5,8,11,14eicosatetraenoic acid)
  15. 15. Unsaturated fatty acids  Pentaenoic acid (5 double bonds)  20:5; 5,8,11,14,17 ω3: timnodonic acid or EPA (all-cis-5,8,11,14,17-eicosapentaenoic acid)*  Hexaenoic acid (6 double bonds)  22:6; 4,7,10,13,16,19 ω3: cervonic acid or DHA (all-cis-4,7,10,13,16,19-docosahexaenoic acid)* Both FAs are found in cold water fish oils
  16. 16. Waxes Waxes are simple lipids which are esters of long chain alcohols and fatty acids. Beeswax is a 30 C alcohol connected to a 16 C fatty acid Waxes are completely water resistant and make the coatings on leaves, skin, feathers, fur, and fruit. They can be used on floors and furniture for the same protecting quality.
  17. 17. 4. Membrane lipids 1) phospholipids - phosphoglyceride: phosphatidyl serine (ethanolamine, choline, inositol) - sphingolipid: spingosine → sphingomyelin 2) glycolipids - sugar-containing lipids - cerebrosides - gangliosides 3) cholesterol
  19. 19. Glycerol phospholipids O O O O R CH2 O O O HC CH2 O R R P OH CH2 O O O HC CH2 O OH O O R CH2 O O O HC CH2 O O CH3 + N CH2 P OH H3C R CH2 CH3 R OH NH2 CH2 P O CH2
  20. 20. O O R CH2 O O R O HC CH2 O CH2 P O OH Phosphotidyl serine NH2 HC COOH O O R CH2 O O R O HC CH2 O HO P O OH CH OH CH Phosphotidyl Inositol CH CH CH CH HO OH OH O O R CH 2 O O R O HC HC P CH 2 O HO OH OH O Phosphatidyl glycerol CH2 HC OH O O O R R CH2 O O O HC CH2 O O OH R HC P OH O CH2 HC OH O O CH P O CH2 O HO Diphosphatidylglycerol (cardiolipin) CH2 O R
  21. 21. O O O H 2C H2 C C H O O P H2 C O H2 C NH2 OH Phosphotidyl Ethanolamine O O O H2C C H O O H2 C O CH3 P H2 C O H2 C OH O N CH3 CH3 Phosphotidyl Choline O HO O H 2C O C H OH O H2 C O O P OH OH HO O OH Phosphotidyl Inositol O O H2C O C H NH2 O H2 C O O P OH H2 C CH C O OH Phosphotidyl Serine
  22. 22. O R H2 C O R O C H OH O H2 C O P H C O OH H2 C C H OH OH O Phosphotidyl Glycerol O O R H2 C R O O C H H2 C O OH O P O OH H C C H H2 C OH O OH P O O H2 C CH O O CH2 R O O Diphosphotidyl Glycerol R
  23. 23. Ether glycerophospholipids  Possess an ether linkage instead of an acyl group at the C-1 position of glycerol  PAF ( platelet activating factor)  A potent mediator in inflammation, allergic response and in shock (also responsible for asthma-like symptom  The ether linkage is stable in either acid or base  Plasmalogens: cis α,β-unsaturated ethers  The alpha/beta unsaturated ether can be hydrolyzed more easily
  24. 24. Ether glycerophospholipids O - O P O H2C O CH O CH3 O CH2 CH2 N -O CH3 O CH3 H2C CH2 H O O CH O CH2 CH2 N CH3 CH2 O C C P CH3 O O H CH3 A choline plasmalogen platelet activating factor or PAF CH3
  25. 25. Phospholipase A1 Phospholipase A2 O O CH2 O R O HC CH2 O O P OH R O X Phospholipase C Phospholipase D SURFACTANT ( DIPALMITOYL PHOSPHATIDYL CHOLINE O O CH2 O PALMITIC O HC CH2 O O P OH PALMITIC H3C N CH2 O CH3 + CH2 CH3
  26. 26. SPHINGOLIPIDS H 3C SPHINGOMYELIN CH2 CH2 CH2 CH2 CH2 CH2 CH2 O CH2 CH2 CH2 CH2 CH2 CH2 CH2 C Palmitic acid HO + Hydrophobic end 1 CH2 R CH2 CH2 NH2 H3C CH2 CH2 CH2 CH2 CH2 CH2 CH CH OH CH2 CH2 CH2 CH2 CH2 CH2 CH CH CH2 Sphingosine OH O C NH R CH CH HC CH O CH2 O CH2 P OH CH3 OH + CH2 N O CH3 CH3 CERAMIDE Hydrophilic end SPHINGOLIPIDS H3C CH2 CH2 CH2 CH2 CH2 CH2 CH2 O CH2 CH2 CH2 CH2 CH2 CH2 CH2 C NH H3C CH2 CH2 CH2 CH2 CH2 CH2 CH CH OH CH2 CH2 CH2 CH2 CH2 CH2 CH CH CH2 Ceramide Acylated Sphingosine O HO Palmitic acid + NH2 OH Sphingosine OH OH O NH R 1 OH CH2 CH2 O CH2 C Ceramide OH Acylated Sphingosine NH R CH CH HC OH CH CH2 OH Ceramide R O 1 NH R OH OH Ceramide
  27. 27. SPHINGOLIPIDS O HO Palmitic acid + NH2 OH Sphingosine OH O NH OH Ceramide OH Acylated Sphingosine R O 1 R OH OH Ceramide
  28. 28. SPHINGOLIPIDS CEREBROSIDES Galactocerebroside R O H3C C H3C CH O OH CH 2 O CH CH OH OH OH Glucocerebroside O R 1 O H3C HN R CH2 HC (CH2) 12 R HO NH C H3C CH CH CH2 O CH OH OH OH OH HO CH 2 O CH (CH 2) 12 OH HO NH Lactosyl ceramide R O H3C C H3C CH CH 2 O CH2 O CH (CH 2) 12 HO NH CH CH OH OH OH HO O O OH CH2 OH OH HO O Trihexosyl ceramide R H3C H3C CH2 NH C CH (CH 2)12 HO CH CH2 HO O CH CH O OH CH2 OH OH OH O O OH CH2 O OH OH CH2 OH
  29. 29. Some Galactocerebrosides are sulfated at position 3 of the galactose CH2 R 1 CH2 CH2 O HO C O NH R CH CH O HC CH OH CH2 H H OH HO H H OSO3H H
  30. 30. GANGLIOSIDES HO HO HO O R NH H2 C Cer (CH2)12 O O Glc OH OH O OH Gal OH GalNAc O NANA NANA CerGlcGalGalNAcGal O C CH3 O H2 C Gal HO HO GM3 O NH GM1 GM2 OH CH2 O CH2 O CH2 O HO OH
  31. 31. OH Globoside Gb3 OH O HO OH OH OH O O HO OH OH O O O HO OH HN O OH OH O HO NH OH Globoside Gb4 OH O O OH O O O HO OH OH OH OH O O HO O OH HN O
  32. 32. THE UNIVERSAL BLOOD GROUP ANTIGENS ARE SPHINGOLIPIDS WHICH ARE EXPRESSED ON THE SURFACE OF ERYTHROCYTES Fuc(a1-2) Gal(B1-4)GalNAc(B) O Cer GalNAc(a1-3) Blood Group A Fuc(a1-2) Gal(B1-4)GalNAc(B) O Cer Gal(a1-3) Blood Group B Fuc(a1-2) Gal(B1-4)GalNAc(B) O Blood Group O Cer
  33. 33. 26 21 CH3 18 12 11 2 9 10 3 8 5 4 Polar Head H 7 CH 16 14 H HO 17 H 19 1 13 CH3 CH2 CH2 CH2 20 22 23 24 15 HC 25 CH3 27 CHOLESTEROL 6 Non polar Head
  34. 34. Steroids
  35. 35. Cholesterol, an important constituent of cell membranes, has a rigid ring system and a short branched hydrocarbon tail. HO Cholesterol Cholesterol is largely hydrophobic. But it has one polar group, a hydroxyl, making it amphipathic. PDB 1N83 cholesterol
  36. 36. HO Cholesterol Cholesterol in membrane Cholesterol inserts into bilayer membranes with its hydroxyl group oriented toward the aqueous phase & its hydrophobic ring system adjacent to fatty acid chains of phospholipids. The OH group of cholesterol forms hydrogen bonds with polar phospholipid head groups.
  37. 37. Interaction with the relatively rigid cholesterol decreases the mobility of hydrocarbon tails of phospholipids. Cholesterol in membrane But the presence of cholesterol in a phospholipid membrane interferes with close packing of fatty acid tails in the crystalline state, and thus inhibits transition to the crystal state. Phospholipid membranes with a high concentration of cholesterol have a fluidity intermediate between the liquid crystal and crystal states.
  38. 38. OUT IN
  39. 39. peripheral Membrane proteins may be classified as:  peripheral  integral  having a lipid anchor lipid anchor lipid bilayer integral Membrane Proteins Peripheral proteins are on the membrane surface. They are water-soluble, with mostly hydrophilic surfaces. Often peripheral proteins can be dislodged by conditions that disrupt ionic & H-bond interactions, e.g., extraction with solutions containing high concentrations of salts, change of pH, and/or chelators that bind divalent cations.
  40. 40. peripheral lipid anchor lipid bilayer integral Membrane Proteins Integral proteins have domains that extend into the hydrocarbon core of the membrane. Often they span the bilayer. Intramembrane domains have largely hydrophobic surfaces, that interact with membrane lipids.
  41. 41. lipid anchor membrane cysteine residue palmitate Some proteins bind to membranes via a covalently attached lipid anchor, that inserts into the bilayer. A protein may link to the cytosolic surface of the plasma membrane via a covalently attached fatty acid (e.g., palmitate or myristate) or an isoprenoid group. Palmitate is usually attached via an ester linkage to the thiol of a cysteine residue. A protein may be released from plasma membrane to cytosol via depalmitoylation, hydrolysis of the ester link.
  42. 42. CH3 CH3 H3C C CH CH2 CH2 C CH3 CH CH2 CH2 C CH CH2 Protein S farnesyl residue linked to protein via cysteine S An isoprenoid such as a farnesyl residue, is attached to some proteins via a thioether linkage to a cysteine thiol. lipid anchor membrane
  43. 43. Glycosylphosphatidylinositols (GPI) are complex glycolipids that attach some proteins to the outer surface of the plasma membrane. The linkage is similar to the following, although the oligosaccharide composition may vary: protein (C-term.) - phosphoethanolamine – mannose - mannose mannose - N-acetylglucosamine – inositol (of PI in membrane) The protein is tethered some distance out from the membrane surface by the long oligosaccharide chain. GPI-linked proteins may be released from the outer cell surface by phospholipases.
  44. 44. Lipid storage diseases     also known as sphingolipidoses genetically acquired due to the deficiency or absence of a catabolic enzyme examples:     Tay Sachs disease Gaucher’s disease Niemann-Pick disease Fabry’s disease 
  45. 45. What are Lipid Storage Diseases? Lipid storage diseases are a group of inherited metabolic disorders in which harmful amounts of fatty materials (called lipids) accumulate in some of the body’s cells and tissues. Over time, this excessive storage of fats can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen, and bone marrow. Lipid storage diseases are inherited from one or both parents who carry a defective gene. Symptoms may appear early in life or develop in the teen or even adult years. Neurological complications of the lipid storage diseases may include ataxia, eye paralysis, brain degeneration, seizures, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, burning pain in the arms and legs, and clouding of the cornea
  46. 46. Genetic defects in ganglioside metabolism  leads to a buildup of gangliosides (ganglioside GM2) in nerve cells, killing them enzyme that hydrolyzes here (beta hexosaminodase) is absent in Tay-Sachs disease Gal NAc Gal Gal Glu NAcNeu CER
  47. 47. Tay-Sachs disease  a fatal disease which is due to the deficiency of     hexosaminidase A activity accumulation of ganglioside GM2 in the brain of infants mental retardation, blindness, inability to swallow a “cherry red “ spot develops on the macula (back of the the eyes) Tay-Sachs children usually die by age 5 and often sooner
  48. 48. Genetic defects in globoside metabolism  Fabry’s disease:  Accumulation of ceramide trihexoside in kidneys of patients who are deficient in lysosomal αgalactosidase A sometimes referred to as ceramide trihexosidase  Skin rash, kidney failure, pains in the lower extremities  Now treated with enzyme replacement therapy: agalsidase beta (Fabrazyme)
  49. 49. Genetic defects in cerebroside metabolism  Krabbe’s disease:  Also known as globoid leukodystrophy  Increased amount of galactocerebroside in the white matter of the brain  Caused by a deficiency in the lysosomal enzyme galactocerebrosidase  Gaucher’s disease: Caused by a deficiency of lysosomal glucocerebrosidase Increase content of glucocerebroside in the spleen and liver Erosion of long bones and pelvis Enzyme replacement therapy is available for the Type I disease (Imiglucerase or Cerezyme)  Also miglustat (Zavesca) – an oral drug which inhibits the enzyme glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids    
  50. 50. Miglustat (Zavesca)
  51. 51. Genetic defects in ganglioside metabolism  Metachromatic leukodystrophy  accumulation of sulfogalactocerebroside (sulfatide) in the central nervous system of patient having a deficiency of a specific sulfatase  mental retardation, nerves stain yellowish-brown with cresyl violet dye (metachromasia)  Generalized gangliosidosis  accumulation of ganglioside GM1  deficiency of GM1 ganglioside: β-galactosidase  mental retardation, liver enlargement, skeletal involvement
  52. 52. Niemann-Pick disease  principal storage substance: sphingomyelin which accumulates in reticuloendothelial cells  enzyme deficiency: sphingomyelinase  liver and spleen enlargement, mental retardation
  53. 53. Prostaglandins and other eicosanoids (prostanoids)  local hormones, unstable, key mediators of inflammation  derivatives of prostanoic acid 9 8 COOH 20 11 12 15 prostanoic acid
  54. 54. Prostaglandins
  55. 55. O O O R O OO O P X H20 phospholipase A2 (enzyme that hydrolyzes at the sn-2 position - inhibited indirectly by corticosteroids) O COOH CH3 COX is inhibibited by aspirin and other NSAIDs very unstable bond prostaglandin synthase (also known as cyclooxygenase) O COOH O PGH2 OH
  56. 56. O COOH O OH PGH2 O HO COOH COOH HO OH PGE2 key mediator of inflammation HO OH PGF2α
  58. 58. Prostacyclins, thromboxanes and leukotrienes  PGH2 in platelets is converted to thromboxane A2 (TXA2) a vasoconstrictor which also promotes platelet aggregation  PGH2 in vascular endothelial cells is converted to PGI2, a vasodilator which inhibits platelet aggregation  Aspirin’s irreversible inhibition of platelet COX leads to its anticoagulant effect
  59. 59. Functions of eicosanoids  Prostaglandins – particularly PGE1 – block gastric production and thus are gastric protection agents  Misoprostol (Cytotec) is a stable PGE1 analog that is used to prevent ulceration by long term NSAID treatment  PGE1 also has vasodilator effects  Alprostadil (PGE1) – used to treat infants with congenital heart defects  Also used in impotance (Muse)
  60. 60. Functions of eicosanoids  PGF2α – causes constriction of the uterus  Carboprost; “Hebamate” (15-Me-PGF2α) – induces abortions  PGE2 is applied locally to help induce labor at term
  61. 61. Leukotrienes Non-peptidoleuktrienes: LTA4 is formed by dehydration of 5-HPETE, and LTB4 by hydrolysis of the epoxide of LTA4 O COOH C5H11 HO COOH LEUKOTRIENE A4 (LTA4) C5H11 OH LEKOTRIENE B4 (LTB4)
  62. 62. Biological activities of leukotrienes 1. LTB4 2. LTC4 3. LTD4 4. LTE4 - potent chemoattractent - mediator of hyperalgesia - growth factor for keratinocytes - constricts lung smooth muscle - promotes capillary leakage 1000 X histamine - constricts smooth muscle; lung - airway hyperactivity - vasoconstriction - 1000 x less potent than LTD4 (except in asthmatics)
  63. 63. Leukotrienes Leukotrienes are derived from arachidonic acid via the enzyme 5-lipoxygenase which converts arachidonic acid to 5-HPETE (5-hydroperoxyeicosatetranoic acid) and subsequently by dehydration to LTA4 OH OH COOH COOH H C5H11 H S Cys gGlu LEUKOTRIENE F4 (LTF4) peptidoleukotrienes C5H11 S Cys Gly gGlu LEUKOTRIENE C4 (LTC4)
  64. 64. Leukotrienes Leukotrienes are synthesized in neutrophils, monocytes, macrophages, mast cells and keratinocytes. Also in lung, spleen, brain and heart. A mixture of LTC4, LTD4 and LTE4 was previously known as the slow-reacting substance of anaphylaxis OH OH COOH COOH H C5H11 H S Cys LEUKOTRIENE E4 (LTE4) peptidoleukotrienes C5H11 S Cys Gly LEUKOTRIENE D4 (LTD4)