Chemistry of Lipids

CHEMISTRY of LIPIDS

Lipid is from the Greek Lipos  -fat

1980s – appearance in scientific debates about the value of  fish or marine oils in the diet

Lard (pork fat), tallow(beef fat) , butterfat  And many more

Cottonseed oil

Triglycerols can be hydrolyzed, saponified, and hydrogenated.

Soaps are made by the saponification of triglycerols.

Phospholipid molecules have very polar or  ionic sites in addition to long hydrocarbon Chains.

Prevalent in the membrane of brain cells

Nonhydrolyzable lipids

Chief constituent in gallstones

 Aid in the digestion of dietary lipids and also in the absorption of the fat Soluble vitamins and the fatty acids from the digestive tract-circulation

Important Steroids

The

terms ―fats‖ and ―oils‖ are commonly used to denote crude lipid mixtures which are obtained from natural sources.

Fats

are widely distributed in plants and animals. In plants they are present in nuts, seeds and oils.

The

nervous system of animals is rich in lipids like cholesterol, phospholipids and glycolipids. Blood contains lipoproteins.

The

fat depots such as subcutaneous tissues, mesenteric tissues, fatty tissues around the kidney and yellow bone marrow contain large amounts of fat.

sources rich in fat are milk, egg, meat, liver, fish oils, nuts, seeds and oils.

Food

Biological Significance of Fats 1. Lipids form one of three main types of foodstuffs and act as fuel in the body.

2. Deposits of fat underneath the skin exert insulating effect to the body. They protect the body from excessive heat or cold. Fat people can withstand heat or cold better  than thin people. 3. The mesenteric fat around organs like kidney provides padding and protect internal organs.

4. Building materials. Breakdown products of fats can be utilized for  building biologically active materials like cholesterol, which in turn can be utilized for synthesis of certain hormones. 5. Lipids supply the essential fatty acids which cannot be synthesized in the body.

6. The nervous system is particularly rich in lipids. 7. Some vitamins like A, D, E and K are fat soluble, hence lipid is needed for absorbing these vitamins. 8. Lipoproteins/phospholipids are impt constituents of many natural membranes like cell walls & mitochondrion.

CLASSIFICATION OF LIPIDS 1. Simple Lipids (a) Fats and Oils (b) Waxes The alcohol in fats is glycerol. The alcohol in waxes is anything other  than glycerol.

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2. Compound lipids (a) Phospholipids (b) Glycolipids (c) Sulpholipids (d) Lipoprotein

3. Derived lipids (a) Fatty acids (b) Alcohols other than glycerol (c) Glycerides (d) Bases * choline * sphingosine * glycerides * serine Substances associated with Lipids: 1. Carotenoids 2. Tocopherols 3. Vitamins A,D,E and K 4. Steroids (cholesterol)

 Animals and vegetable fats are complex mixtures of glycerides, that is they are esters of glycerol and fatty acids. Triglycerides or TAG neutral fats are composed of 3 molecules of fatty acids, esterified to glycerol. A triglyceride is formed by the condensation of one molecule of glycerol with 3 molecules of  fatty acids.

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O CH2 OH + H O-C-R1

O CH2-O-C-R1

CH

O OH + H O-C-R1

O CH-O-C-R1 + 3H2O

CH

O OH + H O-C-R1

O CH2-O-C-R1

Glycerol

Fatty Acid

Simple glyceride

Physical Properties  1. They are greasy to touch and leave an oily impression on paper. 2. They are insoluble in H 2O but soluble in organic solvents liq fat=0.95 3. Sp. Gr. < H 2O; solid fat=0.86 4. Pure glycerides are tasteless, odorless, colorless and neutral in rxn. But after  exposure to air for some time, they become acidic and develop a yellow colour due to partial hydrolysis and oxid‘n of unsat‘d fatty acids in them. 

5. Flavor of butter is due to the presence of  bacterial flora, which is carefully controlled to impart special flavor to butter. The color of  butter, human fat and egg yolk are due to the presence of carotene and xanthophyll contained in them. 6. Hardness or consistency depends upon the relative amounts of saturated and unsaturated fatty acids present. Fats containing sat‘d FA are solid at RT. Fats containing unsat‘d FA are liquid at RT and these are oils. 7. Fats have definite melting points. MP of a fat is always higher than the temp at which it solidifies.

8.

When a liquid fat is placed on water, it spreads uniformly over the surface of water  and if the qtty is sufficiently small, it will form a layer of 1 molecule thickness. The effect is to lower the surface tension and help the transport of fat.

9.

Though fats are insoluble in water, they can be broken down into minute droplets and dispersed in water. This is emulsification.

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Saponification Number  The number of mg KOH required to saponify one gram of fat. It is an indication of the MW of the fat and inversely proportional to it. Human fat has saponification no.=194-196, butter 210-230 and coconut oil 253-262

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Iodine Number  The number of g of iodine taken up by 100 g of fat. Index of saturation; directly proportional to unsat‘d FA content. The higher the iodine no., the higher the degree of unsat‘n

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(Phosphoglycerides and spingomyelins)  Any lipid containing phosphorous is called phospholipid. Phospholipids are good emulsifying agents. They are found in cell membranes and in subcellular structures where lipids and water soluble materials interact. The most common phospholipid is the glycerol phospholipids. They contain glycerol PO4, 2 FA and a N cpd that may be choline, ethanolamine or serine. Ex: lecithins and cephalins

G L —Fatty acid Y C —Fatty acid E R O — P — N L Phospholipid or phosphoglycerides

O CH2 —O-C-R O CH —O-C-R1 O CH2—O-P — N cpd OH

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The most common form of phospholipids and has choline as the Nitrogen compound. O CH2O—C—OR1 O choline  CHO—C—OR2 phosphoglyceride  O CH2O—P—O—CH2CH2N+(CH3)3 OH

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Free choline is a compound with an alcohol group. Its linkage to the phoaphate portion of  a lecithin like that of a glycerol to the phosphate, is that of a phosphate ester. HO—CH2—CH2—N+(CH3)2 choline  Lecithins are req‘d for the normal transport and utilisation of other lipids especially in the liver. Anything which interferes with the synthesis of choline also will block the synthesis of lecithins and thus interrupt the normal transportation of lipids to and from liver leading to accumulation of lipid mat‘l in the liver giving rise to fatty liver.

O CH2O—C—OR1 O cephalin  CHO—C—OR2 (ethanolamine phosphoglyceride) O CH2O—P—O—CH2—CH2—CH2—NH2 Cephalin differs from lecithins with respect to base attached to phosphoric acid. If it is ethanolamine, it is called phosphatidyl ethanolamine or ethanolamine cephalin. If it is amino acid serine, it is called phosphatidyl serine or serine cephalin.

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Cephalin on hydrolysis yields glycerol, fatty acids, H3PO4, ethanolamine or serine. They are found in nerve tissues. Cephalins are impt in the clotting of blood and as sources of H 3PO4 for the formation of new tissues. PLASMALOGENS These compounds structurally resemble lecithins and cephalins, with the result that the normal ester is replaced by the ether linkage on the C1 atom. On treatment with acid they give rise to a long chain fatty aldehyde. These compounds constitute as much as 10% of the phospholipids of the brain and the muscles.

CH2—O—CH=CH—R1 O CH—O—C—R2 O CH2—O—P—O—Base OH

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They are found in large quantities in the brain and nerve tissues. No glycerol is present. On hydrolysis yield a fatty acid, phosphoric acid, choline and a complex aminoalcohol, sphingosine (in place of glycerol). sphingosine fatty acid

P

choline sphingomyelin

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Glycolipids are CHO-glyceride derivatives containing sugar, sphingosine,and a fatty acid. They don‘t contain H3PO 4. If the sugar  component is galactose, the lipid is termed galactolipid. The term cerebroside is used because it is found in large quantities in brain tissues particularly in white matter. sphingosine fatty acid

galactose cerebroside

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Non-saponifiable lipids, biological cpds with diverse physiological activities. All steroids are cpds having a cyclopentanoperhydrophenantrene ring system. The structure of many different types of steroids having greatly varying biological activities is shown below.

Chief constituent in gallstones

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CH2OH

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C=O

O

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HO

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CH3

OH

CH3

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CH3

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Cortisone

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O

CH3

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HO

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CH3

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COOH

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CH3

Cholic Acid

Estrone

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Cholesterol is a light yellow crystalline solid; soluble in CHCl3 and other fat solvents. The – OH group on the 3 rd position can be esterified with fatty acids to form cholesterol esters. This is how cholesterol level in the body is regulated. Cholesterol is the most abundant lipid in the human body. It is synthesized mainly in the liver, adrenal cortex, intestines, testes and skin. Acetyl CoA is the precursor of all C atoms in cholesterol. The level of choles-terol in body fluids is of 1 0 imptce due to its role in the dev‘t of atherosclerosis. Choleste-rol also plays impt role as part of biomembrane.

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Polyunsaturated acids (essential FA) tend to lower the plasma cholesterol level.

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Cholesterol in body fluids can be estimated by color rxns, e.g. Liebermann-Burchard rxn.

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 A sol‘n of chloroform gives a blue or green color, when acetic anhydride and concentrated sulfuric acid are added. This reaction is the basis of a colorimetric estimation of blood cholesterol.

1.

Cholesterol is an impt tissue component; has modulating effect on fluid state of membrane

2.

Because of its conductivity, cholesterol plays impt role in insulating nerves/brain structure

3.

For the transport of FA in the body through the formation of esters of fatty acids.

4.

Neutralizes hemolytic action of a no. of agents, like snake venoms, bacterial toxins

5.

6. 7.

Cholesterol gives rise to provitamin ‗D‘. It is a precursor of cholic acid in the body. It gives rise to sex hormones. LIPOPROTEINS Lipoproteins transport neutral lipids I the blood. These are lipids attached to proteins. These are formed by the combination of proteins with lipids which include the phospholipids lecithin and cephalin, fatty acids, cholesterol, glycerides and fat soluble vitamins. The lipoprotein molecule has lower D than the ordinary protein molecule, due to its combination with lipids.

1. Cell membranes  2. Certain internal structures of cells, such as nucleus, mitochondria and microsome 3. Thromboplastin which converts prothrombin to thrombin 4. Egg yolk contains 2 lipoproteins called αlipovitellin and β-lipovitellin. 5. The film that stabilises the fat droplets in milk  contains lipoproteins. 6. Rhodopsin or visual purple is a combination of  

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a protein opsin and retinal aldehyde of  vitamin A (a fat soluble vitamin). 7. Blood lipoproteins are present in plasma. The lipid fraction consists mainly of cholesterol, phospholipids, neutral fat, traces of fat soluble vitamins and steroid hormone. Lipids such as cholesterol and triglycerides are not soluble in water and are thus need to be complexed to water soluble carrier proteins for  transporting them in the blood between different organs.

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Plasma lipoproteins consist of a neutral lipid core of triglyceride and cholesterol ester that is surrounded and stabilised by free cholesterol protein and phospholipid. The relative proportion of nonpolar lipid, protein and polar  lipid determine the density, size and charge of  the resulting lipoproteins.

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The total plasma lipid is 700-1000 mg per dl. Roughly 1/3 is triglycerides, another 1/3 is cholesterol and the rest 1/3 is phospholipids. These are complexed with proteins to form lipoproteins.

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Chylomicrons are the lipoprotein particles lowest in density and largest in size and contain the most lipid and smallest %age of protein. They transport mainly TG and smaller amounts of PL, cholesterol ester and fat soluble vitamins from intestines to liver and adipose tissues.

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The lipids carried by chylomicro chylomicrons ns are principally in dietary lipids. They are formed in the intestinal mucosa. VLDLs are syntesized in the liver and released into blood. They transport triglycerides synthesized in the liver 

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and cholestrol esters from liver to peripheral tissues.

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Fatty liver occurs liver occurs in conditions in which there is an imbalance between hepatic triacyl glyceride synthesis and the secretion of VLDC. Diseases such as diabetes mellitus and chronic ethanol ingestion can cause fatty liver.

 As VLDL passes through through the circulation their  structure is altered to LDL.

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VLDL are composed mainly of TAG, a set more enriched in cholesterol esters than are

chylomicrons . LDL provides cholesterol for  chylomicrons. cellular needs. LDL promotes coronary heart disease by first penetrating the coronary arte-ry wall and then depositing cholesterol to form atherosclerosis plaque. Estimation of Plasma Lipids The serum lipids tests commonly done are total cholesterol, HDL cholesterol & triglycerides. esti mated colorimetrically colorim etrically.. Total cholesterol is estimated 1. Serum is used for Liebermann-Buchard rxn. Cholesterol in presence of ion H 2SO4, acetic acid and acetic anhydride is oxidized to cholestrapolyenes to give blue green color.

2. More modern is the enzymatic cholesterol oxidase method. Cholesterol is oxidized. The H2O2 produced is split by peroxidase to produce nascent oxygen whichn is used to oxidize a colorless chromogen to a colored product. The plasma cholesterol is distributed to diff  protein fractions. In normal persons, cholesterol level varies from 150 to 220 mg/dl with 70% being esterified cholesterol and 30% free. In the ave. adult male, plasma cholesterol should preferably be below 200 mg/dl. The females have a lower level because of the high estrogen level which also affords protection

atherosclerosis. Normally almost 60% of total cholesterol is LDL, 22% HDL, 13% VLDL and 5% chylomicrons.

HDL and LDL HDL cholesterol is estimated after pptating LDL and VLDL. The LDL cholesterol can be calculated from total cholesterol, HDL cholesterol and serum triglycerides.

LDL Cholesterol=Total Cholesterol- [HDL Chol + TAG/5]

1/5 of the triglyceride value is believed to represent VLDL in fasting plasma. The sample serum should be taken after 14-16 hours of  fasting. Elevated LDL levels have been associated with increased risk of developing coronary artery disease, whereas elevated HDL levels appear to reduce the risk. Women have higher  HDL levels than men (55 vs 45 mg/dl) and this may account for women‘s lower rate of heart disease. Aerobic exercise inc. HDL levels.

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Eicosanoids are products of the metabolism of  the 20-C-polyunsaturated FA arachidonic acid.

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Prostaglandins 

1. Structure  Prostaglandins are analogs of prostanoic acids. Prostanoic acid does not occur natu-rally but is regarded as the parent compound of the prostaglandins for the purpose of nomenclature and Carbon numbering.

9

7

10

5

3

1

COO -

8 6

11

12

14

4

2

16

18

20 CH3

13 15 17 19 THE DOTTED LINE BETWEEN C7 AND C8 INDICATES THAT THE C7 CHAIN ATTACHED TO THE C8 RING PROJECTS BELOW THE PLANE OF THE RING WHEREAS THE C8 CHAIN ATTACHED TO C12 PROJECTS  ABOVE THE PLANE.  ALL NATURALLY OCCURING PROSTAGLANDINS HAVE A HYDROXYL GROUP AT C15 PROJECTING BELOW THE PLANE OF THE RING.

2. Nomenclature  Prostaglandin cpds are abbreviated as PG 3. Function  Prostaglandins are widely distributed in tissues, but role is not yet fully understood.  At very low conc‘ns, they have been shown to modulate a wide range of biologic activities including: (a) smooth muscle contraction & relaxation (b) gastric secretion (c) platelet aggregation (d) inflammatory response (e) response to trophic hormones (f) N d H O retention by kidney tubul

1.

Structure and Nomenclature   Are also analogs of prostanoic acid, but they possess a 6-membered, O-containing ring. R 7  THROMBOXANES ARE  ABBREVIATED TX

O

 AS WITH PROSTAGLANDINS, DIFF

CAPITAL LETTERS ARE USED TO DESIGNATE DIFF

O

R 8  COMBINATIONS OF RING

2. Function  (a) Thromboxane A2 (TXA2) is produced by platelets; it causes contraction of arteries and triggers platelet aggregation. (b) These effects are exactly the opposite of  those caused by prostacyclin (PGI 2), which is produced by the endothelial cells of thevascular system. (c) TXA2 and PGI2 are antagonistic and have a balanced working relationship.

Structure and Nomenclature  HPETEs are hydroxy FA derivatives of arachidonic acid that do not contain a ring structure. Hydroperoxy substitution may occur at positions 5,8,9,11, or 15 and the HPETE is named accordingly. 5-HPETE OOH

COOH It is not clear if  HPETEs are

biologically active but they can be

1. Structure. Formed from HPETEs by lipoxygenase and have a common feature of three conjugated double bonds 2. Nomenclature.  All leukotrienes are abbreviated LT. Those derived from arachidonic acid have a subscript 4 to denote they contain 4= bonds.  An add‘l letter is included to indicate modifications to the C chain of the parent compound. Example: LTA4  and LTB 4  and LTC 4 

3.

Functions  Leukotrienes  are involved in chemotaxis, inflammation, and allergic reactions.

Leukotirene D 4  (LTD4) has been identified as the slow reacting substance of anaphylaxis (SRS-A), w/c causes smooth muscle contraction and is about 1000 x more potent than histamine in constricting the pulmonary airways. SRS-A also increases fluid leakage from small blood vessels & constricts coronary arteries. LTB 4  attracts neutrophils and eosinophils, w/c are found in large nos. at sites of inflammation.