FATTY ACIDS (FAs) SIMPLE AND COMPLEX LIPIDS

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1 FATTY ACIDS (FAs) SIMPLE AND COMPLEX LIPIDS Dicarboxylic acids, ketone bodies. Department of General Chemistry Structure and classification of lipids Lipids can be divided into five categories, on the basis of lipid function 1. Energy-storage lipids (triacylglycerols) 2. Membrane lipids (e.g. phospholipids) 3. Emulsification lipids (bile acids) 4. Messenger lipids (e.g. steroid hormones) 5. Protective-coating lipids (biological waxes) Chemically, lipids are an extremely diverse group of molecules. 1

2 Chemically, lipids are an extremely diverse group of molecules. The simplest lipids are the fatty acids. These are long chain hydrocarbons with carboxyl groups (COOH groups). At physiological ph, the carboxyl group is readily ionized. FA are monocarboxylic acids with a short ( 6 carbon atoms), medium (8-14 carbon atoms), or long ( 14 carbon atoms) aliphatic chain Fatty acids Fatty acids that occur in living systems normally contain an even number of carbon atoms, the hydrocarbon chain is usually unbranched and the length of the chain usually ranges from 12 to 24 carbons. Fatty acids that contain no carbon-carbon double bonds are termed saturated fatty acids; those that contain double bonds are unsaturated fatty acids. Unsaturated fatty acids have one or more double bonds 2

3 Fatty acids Biological important ones are usually linear molecules with an even number of carbon atoms Fatty acids are numbered using either arabic numbers (COOH is 1) or the Greek alphabet (COOH is not given a symbol; adjacent carbon atom areα,β,γ, etc) A few fatty acids with anα-oh group are produced and used structurally by humans FATTY ACIDS CHAIN LENGTH Short chain = less than 6 carbons Medium chain = 6-10 carbons Long chain = 12 or more carbons The shorter the carbon chain, the more liquid the fatty acid is Fatty acids 3

4 Fatty acids common saturated FA s: n = 12: lauric acid (n-dodecanoic acid; C 12:0 ) n = 14: myristic acid (n-tetradecanoic acid; C 14:0 ) n = 16: palmitic acid (n-hexadecanoic acid; C 16:0 ) n = 18; stearic acid (n-octadecanoic acid; C 18:0 ) n = 20; arachidic (eicosanoic acid; C 20:0 ) n= 22; behenic acid n = 24; lignoceric acid Unsaturated fatty acids Monoenoic acids (one double bond): C 16:1 9 ω 7: palmitoleic acid C 18:1 9ω 9: oleic acid C 24:1 15 : ω9 nervonic acid 4

5 Unsaturated Fatty Acids Most naturally occurring fatty acids have cis double bonds and are usually liquid at room temperature Omega families of fatty acids A double bond is indicated by n, where n is a number of the first carbon of the bond Since fatty acids are elongated in vivo from the carboxyl end, biochemists use alternate terminology to assign these fatty acids to families Omega (ω) minus x (or n-x), where x is the number of carbon atoms from the methyl end where the double bond is first encountered. Fatty acids and types of fatty acids Unsaturated fatty acids and double-bond position Several families of unsaturated fats may be recognized by the number of saturated carbon atoms that follow the last double bond (the placement of the methyl end of the chain with respect to the double bond) ω-3 (omega-3 fatty acid) ω-6 (omega-6 fatty acid)

6 Omega-6 and Omega-3 Fatty Acids The first double bond: In vegetable oils is at carbon 6 (omega-6). In fish oils is at carbon 3 (omega-3). Essential Fatty Acids The Essential Fats are a group of fatty acids that are essential to human health. Omega-6 (ω6) Linoleic acid, C 18:2 9,12 Omega-3 (ω3) α Linolenic acid, C 18:3 9,12,15 Omega-6 (ω6) γ Linolenic acid, C 18:3 6,9,12 Omega-6 (ω6) Arachidonic acid, C 20:4 5,8,11,14 Omega 3 and omega 6 fatty acids DHA 6

7 Omega 3 fatty acids Docosahexaenoic acid or DHA is an omega-3 fatty acid with six cis double bonds and 22 carbons (22:6n-3). Eicosapentaenoic acid or EPA is an omega-3 fatty acid with five cis double bonds and 20 carbons (20:5n-3). There is evidence that essential fatty acids (EFAs), and especially polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), play fundamental role in development and proper functioning of the nervous system; Consequently, the EFA composition of membrane phospholipids likely plays a direct role in a variety of cellular and multicellular processes, including inflammation and immunity, with implications for neurodegenerative diseases such as multiple sclerosis (MS) and Parkinson's disease (PD). Function of EFAs Formation of healthy cell membranes Proper development and functioning of the brain and nervous system Production of hormone-like substances called Eicosanoids Thromboxanes Leukotrienes Prostaglandins Responsible for regulating blood pressure, blood viscosity, vasoconstriction, immune and inflammatory responses. 7

8 Lipids Two of the major functions of lipids are to serve as The major form of energy storage in the body The basic structural unit of cellular membranes. Classification of lipids MOST FATTY ACIDS IN HUMANS OCCUR AS TRIACYLGLYCEROLS (TAG) Fatty acids occur primarily as esters of glycerol, when they are stored for future utilization In TAG all three hydroxyl groups on the glycerol are esterified with a fatty acid Glycerol 8

9 The fatty acids present in triacylglycerols are predominantly saturated or monounsaturated. Stereospecific numbering Carbon 2 of triglycerides is frequently asymmetric since C-1 and C-3 may be substituted with different acyl groups By convention we normally draw the hydroxyl group at C-2 to the left and use the designation of sn2 for that particular substituent C-1 and C-3 of the glycerol molecule become sn1 and sn3 respectively MAG and DAG Compounds with one (monoacylglycerols = MAG) or two (diacylglycerols =DAG) acids are present only in relatively minor amounts and occur largely as metabolic intermediates in the biosynthesis and degradation of glycerol-compounds. 9

10 Digestion of triacylglycerols Pancreatic Lipase, which is secreted into the intestine, catalyzes hydrolysis of triacylglycerols at their 1 and 3 positions, forming 1,2-diacylglycerols and then 2-monoacylglycerols (monoglycerides). A protein colipase is required to aid binding of the pancreatic lipase at the lipid-water interface. Monoacylglycerols, fatty acids, and cholesterol are absorbed by intestinal epithelial cells. Within intestinal epithelial cells, triacylglycerols are resynthesized from fatty acids and monoacylglycerols Digestion of Triacylglycerols 29 Digestion of triacylglycerols 10

11 Hydrolysis of TAGs by lipases In hydrolysis, triacylglycerols are split into glycerol and three fatty acids. Saponification and Soap Soaps are: Salts of fatty acids. Formed by saponification, a reaction in which a triacylglycerol reacts with a strong base. O CH 2 CH CH 2 O O O C (CH 2) 16CH 3 O C (CH 2 ) 16 CH 3 O C (CH 2) 16CH NaOH CH 2 OH CH OH CH 2 OH O + 3 Na + - O C (CH 2) 16CH 3 salts of fatty acids (soaps) Saponification reaction Mixtures of soaps Long-chain fatty acids are insoluble in water, but soaps form micelles 11

12 Waxes Waxes are: Esters of saturated fatty acids and long-chain alcohols. Coatings that prevent loss of water by leaves of plants. Waxes Triacontanylpalmitate is the main component of beewax. Palmitic acid (C 16:0 ) is esterified by a C 30 chain, triacontanol (or melissyl alcohol). LIPIDS 12

13 General structure of glycerophospholipids C-2 of phospholipids represents an asymmetric center The stereospecific numbering (sn) system is the best way to designate the different hydroxyl groups in glycerol molecule Saturated C 16 or C 18 FA Phosphodiester linkage Derived from polar alcohol smallest = H (from H-OH) least common in membranes phosphatidic acid Unsaturated C 16 C 20 FA Phosphatidic acid Most phospholipids have a saturated fatty acid on C-1 and an unsaturated fatty acid on C-2 of the glycerol backbone 1,2-diacylglycerol 3-phosphate = Phosphatidic acid 13

14 Phospholipids Phospholipids contain 1,2-Diacylglycerol (DAG) and a base (X) connected by a phosphodiester bridge that links the glycerol backbone to some base, usually a nitrogenous one, such as choline, serine, or ethanolamine DAG Phosphatidylglycerols (PG) These molecules are found in high concentration in mitochondrial membranes and as components of pulmonary surfactant. Phosphatidylglycerol is also a precursor for the synthesis of cardiolipin (diphosphatidylglycerols =DPGs). Phosphatidylglycerols exhibit a net charge of -1 at physiological ph. 14

15 Cardiolipin (diposphatidylglycerol=dpg) Cardiolipin is composed of two molecules of phosphatidic acid linked together covalently through a molecule of glycerol, thus is a very acidic (charge, -2) Cardiolipin is found primarily in the inner membrane of mitochondria and also as components of pulmonary surfactant. These molecules are very acidic, exhibiting a net charge of -2 at physiological ph Lecithin and Cephalin Lecithin and cephalin are glycerophospholipids: Abundant in brain and nerve tissues. Found in egg yolk, wheat germ, and yeast. Phosphatidylcholine (PC) This class of phospholipids is also called the lecithins. Phosphatidylcholine (PC) contains mostly palmitic acid (16:0) or stearic acid (18:0) in the sn-1 position and primarily the unsaturated C18 fatty acids oleic, linoleic or linolenic in the sn-2 position At physiological ph, phosphatidylcholines are neutral zwitterions. 15

16 Phosphatidylcholine and Phosphatidylethanolamine Phosphatidylethanolamine (PE) has the same saturated fatty acid at the sn-1 position but contains more of the long-chain polyunsaturated fatty acids namely 18:2, 20:4 and 22:6 at the sn-2 position PE PC PULMONARY SURFACTANT (COMPOSITION OF SURFACTANT) It is about 90% lipid, of which 90% is phospholipid, of which about 2/3 is 1,2-Dipalmitoylphosphatidylcholine (DPPC). DPPC has important mechanical properties that allows it to act as pulmonary surfactant. The lecithin - dipalmitoyllecithin (DPPC) The dipalmitoyllecithin is a component of lung or pulmonary surfactant. It contains palmitate at both carbon 1(R 1 ) and 2 (R 2 ) of glycerol and is the major (80%) phospholipid found in the extracellular lipid layer lining the pulmonary alveoli. Polar head (choline) 16

17 Dipalmitoylphosphatidylcholine is necessary for normal lung function This lipid decreases the surface tension of the aqueous surface layer of the lung Premature babies develop RDS (respiratory distress syndrome) because of immaturity of their lungs, resulting from a deficiency of pulmonary surfactant Phosphatidylserine (PS) Phosphatidylserine (PS) has a net charge -1, causing it to be an acidic phospholipids Phosphatidylinositol (PI) These molecules contain almost exclusively stearic acid at carbon 1 and arachidonic acid at carbon 2. Phosphatidylinositols composed exclusively of non-phosphorylated inositol exhibit a net charge of -1 at physiological ph. 17

18 Phosphatidylinositol (PI) These molecules exist in membranes with various levels of phosphate esterified to the hydroxyl of the inositol. Molecules with phosphorylated inositol are termed polyphosphoinositides. The polyphosphoinositides are important intracellular transducers of signals emanating from the plasma membrane Plasmalogens Plasmalogens are compounds in which O-(1-Alkenyl) substituents occur at C-1 of the sn-glyceryl moiety of phosphoglycerides in combination with an O-acyl residue esterified to the C-2 position Plasmalogens Relatively large amounts of ethanolamine plasmalogen occur in myelin with lesser amounts in heart muscle, where choline plasmalogen is abundant Plasmalogen has one etherlinked alkenyl chain 18

19 Structure of plasmalogen platelet activating factor (PAF) Platelet-activating factor (PAF) or 1-alkyl-2-acetyl-sn-glycero-3- phosphocholine is an ether analogue of phosphatidylcholine. PAF contains an O-alkyl moiety at sn-1 and an acetyl residue instead of a long-chain fatty acid in position 2 of the glycerol moiety PAF is a major mediator of hypersensitivity, acute inflammatory reactions and anaphylactic shock DEGRADATION OF PHOSPHOLIPIDS The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice. A number of toxins and venoms have phospholipase activity, and several pathogenic bacteria (Baccili) produce phospholipases that dissolve cell membranes and allow the spread of infection. Sphingomyelin is degraded by the lysosomal phospholipase, sphingomyelinase. Action of phospholipases Phospholipases A 1 and A 2 hydrolyze the ester bonds at C-1 and C-2 Phospholipases C and D each split one of phosphodiester bonds in the head group 19

20 Phospholipase A 2 Phospholipase A 2 is also an important enzyme, whose activity is responsible for the release of arachidonic acid from the C-2 position of membrane phospholipids. The released arachidonate is then a substrate for the synthesis of the prostaglandins and leukotrienes. Lysophospholipid Eastern diamondback rattlesnake Cobra and bee venoms contain Phospholipase A2. These venoms, when injected into the blood, produce lysophospholipids that disrupt cellular membranes and lyse blood cells. Indian cobras kill several thousand people each year. Sphingolipids The sphingolipids include the sphingomyelins and glycosphingolipids (the cerebrosides, sulfatides, globosides and gangliosides). Sphingomyelins are the only sphingolipid that are phospholipids. Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath. 20

21 Sphingolipids Also major component of membranes Phospholipid or glycolipid (depends on polar group) Derivatives of sphingosine (instead of glycerol) C 18 amino alcohol Ceramide Acylated amine Parent compound of most abundant sphingolipids Polar head group derivatives Phosphodiester or glycosididic or linkage Sphingosine trans-1,3-dihydroxy-2-amino-4-octadecene Sphingosine possesses two asymmetric carbon atoms (position C-2 and C-3) CERAMIDES are fatty acid amide derivatives of sphingosine = N-acylsphingosine CERAMIDE = N-acylsphingosine 21

22 Sphingolipids Also major component of membranes Phospholipid or glycolipid (depends on polar group) Derivatives of sphingosine (instead of glycerol) C 18 amino alcohol Ceramide Acylated amine Parent compound of most abundant sphingolipids Polar head group derivatives Phosphodiester or glycosididic or linkage 22

23 Structure of sphingomyelin Sphingomyelins are sphingolipids that are also phospholipids. Sphingomyelins are important structural lipid components of nerve cell membranes. The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine. Glycosphingolipids Glycosphingolipids contain monosaccharides bonded to the OH of sphingosine by a glycosidic bond. Cerebrosides contain only one monosaccharide. GLYCOLIPIDS 23

24 GLYCOLIPIDS Cerebrosides One sugar molecule Galactocerebroside in neuronal membranes Glucocerebrosides elsewhere in the body Sulfatides or sulfogalactocerebrosides A sulfuric acid ester of galactocerebroside Globosides: ceramide oligosaccharides Lactosylceramide 2 sugars ( eg. lactose) Gangliosides Have a more complex oligosaccharide attached Biological functions: cell-cell recognition; receptors for hormones Structure of cerebroside Cerebrosides have a single sugar group linked to ceramide. The most common of these is galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides). Galactocerebroside Galactocerebrosides are found predominantly in neuronal cell membranes. 24

25 Major fatty acids in cerebrosides contain 24 carbons Lignoceric acid CH 3 (CH 2 ) 22 COOH cerebronic acid, hydroxynervonic acid and nervonic acid are constituents of the ceramide part of cerebrosides (glycosphingolipids found mainly in nervous tissue) Major fatty acids in cerebrosides 2-hydroxytetracosanoic acid (cerebronic acid) and 2-hydroxy-15-tetracosenoic acid (hydroxynervonic acid) are constituents of the ceramide part of cerebrosides (glycosphingolipids found mainly in nervous tissue) SULFATIDES This group (known also as cerebroside 3-sulfate) is mainly formed of 3-sulfate esters of galactosyl-cerebrosides (galactosyl-3-sulfate esters) and is found in mammalian tissues as the corresponding cerebroside group. Excess accumulation of sulfatides is observed in sulfatide lipidosis (metachromatic leukodystrophy). 25

26 Gangliosides Gangliosides are very similar to globosides except that they also contain NANA in varying amounts. The specific names for gangliosides are a key to their structure. The letter G refers to ganglioside, and the subscripts M, D, T and Q indicate that the molecule contains mono-, di-, tri and quatra(tetra)-sialic acid. The numerical subscripts 1, 2 and 3 refer to the carbohydrate sequence that is attached to ceramide; 1 stands for GalGalNAcGalGlc-ceramide, 2 for GalNAcGalGlc-ceramide and 3 for GalGlc-ceramide. Gangliosides Nomenclature of dicarboxylic acids 26

27 Major dicarboxylic acids of Krebs cycle Oxaloacetic Acid Malic Acid Succinic Acid Fumaric acid Citric acid The three ketone bodies Acetoacetate Acetone β-hydroxybutyrate 27

28 Reactions of Ketogenesis Ketone bodies 82 MITOCHONDRIUM Fatty acid 2 Acetyl oxidation to β-oxidation (excess CoA CO 2 Thiolase acetyl CoA) Acetoacetyl CoA Ketone body formation acetyl CoA HMG-CoA synthase (ketogenesis) in liver mitochondria from excess CoA acetyl CoA derived from the Hydroxymethylglutaryl CoA (HMGCoA) β-oxidation of fatty acids acetyl CoA (non-enzymatic) Acetone CoA HMG-CoA-lyase Acetoacetate NADH β-hydroxybutyrate dehydrogenase NAD + β-hydroxybutyrate Citric acid cycle Ketone bodies are a water-soluble, transportable form of acetyl units Acetoacetate is activated by the transfer of CoA from succinyl CoA in a reaction catalyzed by a specific CoA transferase. Acetoacetyl CoA is cleaved by thiolase to yield two molecules of acetyl CoA (enter the citric acid cycle). CoA transferase is present in all tissues except liver 28

29 Ketogenesis Ketone bodies can be transported through the circulatory system. During times of starvation ketone bodies act as the major source of energy for many tissues, including the brain. In these tissues reconversion of ketone bodies to acetyl-coa inside the mitochondria provides metabolic energy Clinical Significance of Ketogenesis The production of ketone bodies occurs at a relatively low rate during normal feeding and under conditions of normal physiological status. Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-coa generated from fatty acid oxidation. This allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain. 29

30 Utilization of Ketone Bodies Liver produces Ketone bodies Liver cannot use acetoacetate as fuel ( lacks enzyme for the conversion of acetoacetate to acetoacetylcoa AcetoacetylCoA is converted to 2 acetylcoa which are oxidized by the TCA Increased Ketogenesis Conditions Starvation Severe DM Rapid mobilization of fat Result to ketonemia ketoacidosis LIPIDS DENTINE: % Cholesterol and cholesterol esters Glycerolipids (tri-,di- and monoglycerides) Phospholipids DENTAL PULP: 57.4% phospholipids and 42.6 simple lipid CARBOXYLIC ACIDS: Dentine: citric and lactic acid 30

31 Structure of the following compounds are obligatory for the control test of fatty acids and simple and complex lipids Fatty acid structures: palmitic, stearic, palmitoleic, oleic, linoleic, α and γ linolenic, arachidonic (omega family of FAs) Monoacylglycerols, diacylglycerols and triacylglycerols with different type of fatty acids Saponification reaction Phosphatidic acid, phosphatidylcholine (lecithin), lysophosphatidylcholine, phosphatidylethanolamine (cephalin), phosphatidylserine, plasmalogen, platelet activating factor (PAF) Sphingosine and ceramide, sphingomyelin, cerebroside Dicarboxylic acids: Oxaloacetate, Malate, Succinate, Fumarate, and Citric acid Ketone bodies: Acetoacetate, Acetone, β-hydroxybutyrate 31