lipid chemistry

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Course contents1. Define and classify lipids and describe their

biochemical function.2. Define and classify fatty acids and describe

their biochemical functions.3. List and describe the function of essential

fatty acids.4. Describe the structure and biochemical

function of phospholipids glycolipids sphingolipids.

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5. Discuss Eicosanoides and their function in health and disease.

6. Describe steroids and their biochemical role.7. Define cholesterol and describe its structure

chemistry and function. 8. Discuss lipid peroxidation and its significance.

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DefinitionHeterogeneous group of • water insoluble • organic molecules• That can be extracted from the

tissues by nonpolar solvents

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lipids• Related to each other more by

their physical properties than chemical nature

• all have diverse chemical structures and functions

• major common feature is that all are relatively insoluble in water

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Biological importance 1• High energy value One gm of fat supplies 9.1 Kcal when

oxidized in human body, so important dietary ingredient

• Best form of stored energy in body in adipose tissues

• Fat soluble vitamins & • Essential fatty acids are carried in fat of

natural food• Decrease gastric motility[decrease

hunger level]• High satiety value

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Biological importance 2• Stored in adipose tissues under

skin & around organs, – Thermal insulator– protecting, supporting them – also gives contours to body

• Electrical insulator in myelinated nerves, cause rapid

propagation of depolarization wave

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• Combination of lipids & proteins in mitochondria & cell membrane are important constituent.

• lipoproteins is way of transporting lipids in blood

• Precursors of e.g cholesterol & vitamin D3• Receptors • function in signal transduction• Blood group specificity, organ & tissue

specificity as well• Hormone like function

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Biomedical importance• Study of lipid biochemistry

necessary in understanding – Atherosclerosis– Obesity– Diabetes mellitis – Hyperlipidemias – Hyperglycaemias – Role of polyunsaturated fatty

acids in nutrition & health

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No single internationally accepted Classification

Lipids in diet

TRIACYLGLYCEROL :MOST OF DIETARY CONSTITUENT.PHOPHOLIPIDSCHOLESTEROL

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Classification of lipids• SIMPLE LIPIDS • COMPOUND or COMPLEX

LIPIDS

• DERIVED, PRECURSOR or ASSOCITED LIPIDS

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lipids

simple compound derived

fats waxes phospholipids NonphospholipidsGlycolipidssulfolipids

Sphingophospholipids glyceroPhospholipids

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SIMPLE LIPIDS

Esters of fatty acids & alcoholfatty acids & alcohol may differ Esters

compound formed by condensation

of an acids & alcohol

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Esters formation R-COOH + R-OH

O // H2O + R - C -O-R

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SIMPLE LIPIDS1. Fats 2. Waxes Fats• Are Esters of fatty acids & alcohol

Glycerol• Oils are fats in liquid state• Neutral fats, triglycerides,

triacylglycerol - same

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waxes• Are Esters of fatty acids & alcohol

other than glycerol• Higher molecular weight

monohydric alcohol is present

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Phospholipids1. GlyceroPhospholipids Glycerol (alcohol) + fatty acids + phosphate2. Sphingophospho lipids Sphingosine (alcohol) + fatty acids + phosphate

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DERIVED, PRECURSOR or ASSOCIATED LIPIDS

Include• Hydrolytic product of above

mentioned compound Diacyle glycerol• Precursor Sterols• Associated Prostaglandin

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Fatty acids

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Fatty acids(structure)

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Fatty Acids as Stored Energy

• Fatty acids are the body’s principal form of stored energy

• Carbon almost completely reduced as CH2

• Very closely packed in storage tissues - not hydrated as sugars are

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Dietary Fatty Acids

• Comprise 30-60% of caloric intake in average American diet

• Triacylglycerols, phospholipids, sterol esters

• Principal sources: dairy products, meats

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Fatty acids structure• Hydrocarbon chain with carboxylic group

at one end (Monocarboxylic acid)• Ranging in chain length from 4 to usually

24 Carbon atoms• Occurring in Triglycerides• Generally contain even number of Carbon

atoms• Below 8 C chain are liquid at room

temperature

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structure of Fatty Acids •At physiologic pH, the COOH group

ionizes to COO- ( pKa ~ 4.8 for COOH)•Physical & physiological properties of fatty acids reflect chain length & degree of unsaturation • Short and medium chain FAs are amphipathic (both hydrophilic and hydrophobic regions) and partially soluble in water

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• Long chain fatty acids are highly insoluble in water

(must be transported in association with plasma proteins)

• Unusual fatty acids with branched or ring-containing chains are found in some species

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functions• Stored as Triacylglycerols • Function as one of the major fuel sources for energy• Essential fatty acids• Precurssor of Eicosanoids

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Types of fatty acidsFatty acids

Essential Saturated

UnsaturatedNon-essential

Cis isomer Trans isomer

Odd chainEven Chain

StraightBranched

Short chainMedium

Long

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Saturated • Fatty acids chains that

contain only carbon-carbon single bonds

Unsaturated • Those molecules that contain

one or more double bonds

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Palmitic acid 16 : 0 CH3(CH2)14COOH 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2

1O H H H H H H H H H H H H H H H // H-C–C–C–C–C–C–C–C–C–C–C–C–C–C–C–C-

OH H H H H H H H H H H H H H H H

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Abbreviations for fatty acids (16 : 1 9)

• The number to the left of the colon is the total number of carbon atoms

• and the number to the right is the number of double bonds.

• A superscript denotes the placement of a double bond.

• For example, ∆9 signifies that there is a double bonds between carbons 9 and 10.

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Palmitoleic acid 16 : 1 9

16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 O H H H H H H H H H H H H H H H // H-C–C–C–C–C–C–C–C–C–C–C–C–C–C–C–C-

OH H H H H H H H H H H H H H

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Isomeric forms: Cis and trans• double bonds are rigid structures,

molecules that contain them can occur in two isomeric forms

Cis-isomers • similar or identical groups are on

the same side of a double bond.Trans-isomer • groups are on opposite sides of a

double bond

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• The double bonds in most naturally occurring fatty acids are in a cis configuration.

• The presence of a cis double bond causes an inflexible “kink” in a fatty acid chain.

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Isomeric forms of unsaturated fatty acids

CH3 COOH COOH R R R H C=C C=C H H H R CH3

Cis. Isomer Trans isomer

1200

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O॥C-O-

O॥C-O-

Saturated bonds

unsaturated bondsCis configuration

Saturated fattyacid unSaturated fattyacid

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• Because of KINk unsaturated fatty acids do not pack as closely together as saturated fatty acids.

• Less energy is required to disrupt the intermolecular forces between unsaturated fatty acids.

• Therefore, they have lower melting points and are liquids at room temperature.

• For example, a sample of palmitic acid (16:0), a saturated fatty acid, melts at 63oC, whereas palmitoeic acid (16:1∆9) melts at 0oC.

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• Fatty acids with one double bond monounsaturated

• two or more double bonds occur in fatty acids usually separated by methylene groups (-CH2-), they are polyunsaturated.

• The monounsaturated fatty acid oleic acid (18:1∆9) and the polyunsaturated linoleic acid (18:2∆9, 12) are among the most abundant in living organisms.

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• presence of one or more double bonds in a fatty acid makes it susceptible to oxidative attack.

• tendency of oils to become rancid.

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Some naturally occurring saturated fatty acids in animals

NameNo. of carbon

structure abbreviation

Palmitic acid 16 CH3(CH2)14COO

H 16:0

Stearic acid 18 CH3(CH2)16COO

H 18:0

Arachidic acid 20 CH3(CH2)18COO

H 20:0

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Some naturally occurring unsaturated fatty acids in animalsname No.

of carbon

Structure (sat)x Abbreviat-ion

oleic acid 18 CH3(CH2)16COO

H 18:19

linoleic acid

18 CH3(CH2)16COOH

18:29,12

Arachid-onic acid

20 CH3(CH2)18COOH

20:45,8,11,14

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Essential Fatty Acids• Organisms such as plants and bacteria

can synthesize the entire fatty acids they require.

• Mammals obtain most of their fatty acids from dietary sources. However, these organisms can synthesize saturated fatty acids and some monounsaturated fatty acids. They can also modify some dietary fatty acids by adding two-carbon units and introducing some double bonds.

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Definition• Nonessential Fatty acids that can be

synthesized in body • Essential fatty acids must be

obtained from the diet, Because mammals do not possess the enzymes required to synthesize them

• linoleic (18:2∆9, 12) • linolenic (18:3∆9, 12, 15) acids• Arachidonic acid(20:45,8,11,14)

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Linolenic acid:CH3-CH2-CH=CH-CH2-CH=CH-CH2-CH=CH-(CH2)7-COOH

• Linoleic Acid has 2 instead of 3 double bonds

• Arachidonic and Eicosapentaenoic acids produced from these.

• Some species not able to do these conversions.

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sources• Rich sources of essential fatty

acids include some vegetable oils, nuts, and seeds.

• Linoleic and linolenic – green plants, animal fats, seed oils

• Arachidonic – not found in plants.

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Functions• Important in cell membranes,

contributing to proper membrane structure,

• linolenic and linoleic acids are precursors of several important metabolites.

• The most-researched examples of fatty acid derivatives are the eicosanoids i.e Precursors for prostaglandins and leukotrienes

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Essential Fatty Acids• Discovered when animals fed on fat

free diets but• adequate energy, protein, minerals,

and vitamins developed symptoms.• Symptoms disappeared with

addition of fat.• Animals cannot make some double

bonds, so fatty acids required in the diet.

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Deficiency Symptoms• Loss of hair• Dermatitis • Poor growth and reproduction• kidney problems• Poor healing• Dehydration• Degeneration of liver• Immune system failure• Thrombocytopenia [ a relative

decrease of platelets in blood]

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Reactions of fatty acids1. Esters formation• Fatty acids react with Alcohols to

form Esters• This reactions reversible; that is,

under appropriate conditions a fatty acid Ester can react with water to produce a fatty acid and an alcohol.

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2. Hydrogenation reactions• Unsaturated fatty acids with double

bonds can undergo hydrogenation reactions to form saturated fatty acids.

3. Oxidative attack • unsaturated fatty aids are susceptible to

oxidative attack.• Rancidity, development of unpleasant

odour & taste in lipids when exposed to air due to ketoacids & short chain fatty acids

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Reactions of fattyacids4. Acylated proteins• Certain fatty acids (primarily

myristic and palmitic acids) are covalently attached to a wide variety of eukaryotic proteins.

• Fatty acids are transported from fat cells to body cells esterified to serum proteins and enter cells via acyl transfer reactions.

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Simple lipids

Triacylglycerolwaxes

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Structure of triacylglycerols• Tricylglycerols are esters of

glycerol with three fatty acid molecules

• Glycerides with one or two fatty acid groups, called Monoacylglycrols and Diacylglycerols, respectively, are metabolic intermediates. They are normally present in small amounts

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O

॥ ester O CH2-O- C- R1 bond ॥ R2 -C-O-CH O

॥ CH2-O- C-R3

Triacylglycerol

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Structure of Triacylglycerols(TAG)• The carboxyl group of Three fatty acid is

joined to glycerol through a covalent bond (ester)

• Most triacylglycerol molecules contain fatty acids of varying lengths, which may be unsaturated, saturated, or a combination

• Loss of negative charge generates “neutral fat”

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• FAs of TGs usually vary:•fatty acid on carbon 1 is usually saturated

•fatty acid on carbon 2 usually unsaturated

• fatty acid on carbon 3 can be either saturated or unsaturated

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• Carbon 1 & 3 of glycerol are not identical (3 D structure)

• Enzyme can distinguish them readily & are specific to them

• Example, Glycerol is always

phosphorylated at C # 3 by Glycerol kinase

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• Depending on their fatty acid compositions, TAG mixtures referred to as fats or oils.

• Fats, solid at room temperature, contain a large proportion of saturated fatty acids.

• Oils are liquid at room temperature because of their relatively high unsaturated fatty acid content

• Unsaturated FAs decrease Tm

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• In animals, Triacylglycerol (usually referred to as fat) have several roles.

storage • Major• Triacylglycerol molecules store

energy more efficiently than glycogen for several reasons:

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Triacylglycerol, best form of energy stores.

1. Because Triacylglycerol are hydrophobic, they coalesce into compact, anhydrous droplets.

• Glycogen (the other major energy storage molecule) binds a substantial amount of water

• Triacylglycerols store an equivalent amount of energy in about one-eighth glycogen’s volume.

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Triacylglycerol,best form of energy stores.

2. Triacylglycerol molecules are less oxidized than carbohydrate molecules. Therefore, triacylglycerols release more energy (38.9 kj/g of fat compared with 17.2 kj/g of carbohydrate) when they are degraded.

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Insulation • A second important function of fat

is to provide insulation in low temperatures. Fat is a poor conductor of heat. Because adipose tissue, with its high triacylglycerol content, is found throughout the body (especially underneath the skin), it prevents heat loss.

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• Are Carrier of fatty acids.• Finally, in some animals fat

molecules secreted by specialized glands make fur or feathers water-repellent.

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Triacylglycerols in plants,• In plants, Triacylglycerols

constitute an important energy & and fatty acids (e.g., oleic and linoleic), reserve (plant oils)

• Seeds rich in oil include peanut, corn, palm, sunflower, and soybean. Olives have high oil content

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WAX ESTERS• Esters composed of long-chain

fatty acids and long-chain alcohols are prominent constituents of most waxes.

• They are protective coatings on leaves, stems, and fruits of plants and the skin and fur of animals.

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Examples of waxes • Well-known examples of waxes

include carnauba wax, produced by the leaves of the Brazilian wax palm, and Beeswax.

• Triacontyl hexadecanoate is one of several important wax esters in beeswax.

• Waxes also contain aldehyde and sterols (steroid alcohol).

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Compound lipids1. PHOSPHOLIPIDS2. NON-PHOSPHOLIPIDS

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COMPOUND or COMPLEX LIPIDSEsters of fatty acids & alcohol

containing an additional group. subdivided as,

1. Phospholipids additional group is phosphate 2. Nonphospholipids

– Glycolipids – Sulfolipids – Gangliosides

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PHOSPHOLIPIDS (Biological role)• They are first and foremost structural

components of membranes. • Several phospholipids are emulsifying

agents and surface active agents.• (A surface active agent is a substance

that lowers the surface tension of a liquid, usually water, so that it spreads out over a surface.) Phospholipids are suited to these roles because they are Amphipathic molecules.

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Amphipathic• Despite their structural differences,

all phospholipids have hydrophobic and hydrophilic domains.

• The hydrophobic domain is composed largely of the hydrocarbon chains of fatty acids;

• the hydrophilic domain, called a polar head group, contains Phosphate and other charged or polar groups.

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• When phospholipids are suspended in water, they spontaneously rearrange into ordered structures.

• Phospholipids hydrophobic groups are buried in the interior to exclude water. Simultaneously, hydrophilic polar head groups are oriented so that they are exposed to water.

• When Phospholipids molecules are present in sufficient concentration, they form bimolecular layers. This property of phospholipids (and other amphipathic lipid molecules) is the basis of membrane structure

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There are two types of phospholipids1. GlyceroPhospholipids

Phosphoglycerides Glycerol (alcohol) + fatty acids + phosphate

2. Sphingophospho lipidssphingocyelins. Sphingosine (alcohol) + fatty acids + phosphate

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GlyceroPhospholipids

Phosphoglycerides are the most numerous phospholipids molecules found in cell membranes.

• Phosphatidic acid• Phosphatidyl cholin (Lecithin)• Phosphatidyl ethanolamin• Phosphatidyl Serine• Cardiolipin• Plasmalogen

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GlyceroPhospholipids (cont)• Phosphatidyl Inositol• Platelete activating factor

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Membrane Phospholipids• Phosphatidyl choline is major lipids• Outer membrane --- Phosphatidyl

Choline & Sphingomyline are dominant

• Inner membrane---Phosphatidylserine & Phosphatidyl ethanolamine

• Phosphatidyl inositol (only in inner membrane) as second messenger

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• The most common fatty acids in the Phosphoglycerides have between16 and 20 carbons.

• Saturated fatty acids usually occur at C-1 of glycerol.

• The fatty acid substituent at C-2 is usually unsaturated.

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O ॥ O CH2-O- C-R1

॥ R 2-C-O-CH O ॥ CH2-O- P-O-

। O-

Phosphatidic Acid

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Phosphatidic acid• The simplest Phosphoglyceride,• is the precursor for all other

Phosphoglyceride molecules.• is composed of Glycerol-3-

phosphate that is esterified with two fatty acids.

• Phosphoglyceride molecules are classified according to which nitrogenous base becomes esterified to the phosphate group.

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O ॥ O CH2-O- C-R1 ॥ R 2-C-O-CH O ॥ CH2-O-P-O– -CH2CH2N+

(CH3)3 । O-

Phosphatidyl cholin(Lecithin)

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Lecithin• Membrane sturcture.• Abundant PL in serum & bile• Amulsifying agent• Is part of Surfactant on alveolar

membranes, lower surface tension.• Synthesized in later period of pregnancy• Premature birth may results in lung

collapse• Respiratory distress syndrome

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Clinical corelation• Lecithin/Sphingomyelin ratio in

amniotic fluid predicts about lung function & hence survival of baby before delivery

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O ॥ CH2-O- C-R1 OH-CH O ॥ CH2-O-P-O-CH2CH2N+(CH3)3 । O-

Lysophosphatidyl cholin(LysoLecithin)

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LysoLecithin• Enzymatic removal of fatty acid from C1 or

C2 of lecithin• 1 acyl radical only • Important in interconversion &

metabolism of phospholipids• Phospholipase A, is present in snake venom• LysoLecithin causes hemolysis of

erythrocytes• Found in oxidized lipoproteins,implicated in

some of their effects in promoting atherosclerosis

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O ॥ O CH2-O- C-R1 ॥ R 2-C-O-CH O ॥ CH2-O-P-O-CH2CH2-NH3

+

। O-

Phosphatidyl Ethanolamin(Cephalin)

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Phosphatidyl Ethanolamin (Cephalin)

• Resembles Lecithin in function & found in association with it

• Head groups differ• Named, separated in high

concentration from brain tissues

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O

॥ O CH2-O- C-R1 ॥ R 2-C-O-CH O NH3

+

॥ । CH2-O-P-O-CH2CH । । O- COO-

Phosphatidyl Serine

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O O ॥ ॥ O CH2-O- C-R1R 4-C-O-CH O ॥ ॥R 2-C-O-CH O CH2-O- C-R3 ॥ OH

CH2-O- P-O-CH2-C-CH2-O- P-CH2 । H O-

Cardiolipin

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Cardiolipin• Diphosphatidyl glycerol• 2 phosphatidic acid esterified

through phosphate to a glycerol• Only GPL in human i-e antigenic• In inner mitochondrial membrane

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O H2C-O- CH=CH-R1 ॥ R 2-C-O-CH O ॥ CH2-O-P-O– -CH2CH2-NH3

+

। O-

Plasmalogen(Phosphatidyl Ethanolamin)

Ether linkage

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Plasmalogen (Phosphatidyl Ethanolamin)

• Carbon 1 of glycerol has a vinyl ether instead of fatty acid

• Unsaturated alkyl group• Otherwise identical to Phosphatidyl

Ethanolamin & Cholin • Skeletal muscle, brain(10%), heart

liver & platelets • Resistant to Phosoholipases

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Platelets activating factor (PAF)• Is a related to Plasmalogen compound• vinyl ether with saturated alkyl group

at C1 & Acetyl at C2• One of most potent biomolecule• Released from Basophils• Binding to receptors triggers potent

– Thrombotic– Inflammatory events

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PAF• Stimulates the aggregation of Platelets • Helps in clotting of blood• Mediates

– hypersensitivity – Anaphylactic shock– Acute inflammatory reaction

• stimulates inflammatory cells to produce superoxides to kill becteria

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Phosphatidylinositol (2nd messanger)• Phosphatidyl-4,5-bisphosphate

(PIP2) A derivative of phosphatidylionositol, is found in plasma membranes, in only small amounts.

• PIP2 is now recognized as an important component of intracellular signal transduction.

• The Phosphatidylinositol cycle, initiated when certain hormones bind to membrane receptors

• Carrier of Arachidonic acid in membrane

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SPHINGOLIPIDS

• Sphingolipids are important components of animal and plant membranes.

• All sphingolipid molecules contain long-chain amino alcohol.

• In animals this alcohol is primarily sphingosine.

• Phytosphingosine is found in plant sphingolipids.

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OH O । H ॥ CH3-(CH2)12-CH=CH-CH-CH-N-C-R । CH2 । O । O=P-O-

।Sphingomyelin O- CH2- CH2-N

(CH3)

Fatty acidSphingosine

Ceramide

Choline

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Ceramide• The core of each type of

Sphingolipid is Ceramide• a fatty acid amide derivative of

sphingosine.• In Sphingomyelin, the 1-Hydroxyl

group of Ceramides esterified to the Phosphate group of Phosphorylcholine or Phosphorylethanolamine.

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Sphingomylein• Is found in most animal cell membranes. • However, as its name suggests,

Sphingomyelin is found in greatest abundance in the Myelin sheath of nerve cells. (The myelin sheath is formed by successive wrappings of the cell membrane of a specialized myelinating cell around a nerve cell axon.

• Its insulating properties facilitate the rapid transmission of nerve impulses.

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Non phospholipids (Glycosphingolipids)• The Ceramides are also precursors for the

Glycolipids or Glycosphingolipids.• In Glycolipids a monosaccharide,

disaccharide, or oligosaccharide is attached to a ceramides through an O-glycosidic linkage.

• Glycolipids also differ from Sphingomyelin in that they contain no phosphate

• Particularly in outer leaf of plasma memb

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OH । H CH3-(CH2)12-CH=CH-CH-CH-N- O-CH2

Fatty acid

Sphingosine

Ceramide

HHH

HHCH2OH

OHOH

OH

OGalactose

Galactocerebroside

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Glycolipid classes• The most important glycolipid

classes are the • Cerebrosides • Sulfatides• Gangliosides

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Cerebrosides (Neutral)• Are Sphingolipids in which the head

group is a monosaccharide.• These molecules, unlike phospholipids,

are nonionic.• Galactocerebrosides the most common

example of this class, are almost entirely found in the cell membranes of the brain, may contain Cerebronic acid(C24)

• Globosides (Lactosylceramide)

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Sulfatide (Acidic)• If a Cerebroside is sulfated, it is

referred to as a sulfatide.• Sulfatides are negatively charged

at physiological pH.• Found in nerve tissue & kidneys

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Gangliosides (Acidic)

• Sphingolipids that possess Oligosaccharide groups with one or more Sialic acid residues are called Gangliosides

• Although were first isolated from nerve tissues, they also occur in most other animal tissues.

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Name of Gangliosides • This includes subscript letter and

numbers. • The letters M, D, and T indicate

whether the molecule contains one, two, or three sialic acid residues respectively.

• The number is designated on basis of chromatographic migration

• The Tay-Sachs Ganglioside is GM2

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• Certain Glycolipid molecules may bind bacterial toxins, as well as bacterial cells, to animal cell membranes.

• For example, the toxins that cause Cholera, Tetanus, and Botulism bind to Glycolipid cell membrane receptors.

• The role of Glycolipids is still unclear.

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• Bacteria that have been shown to bind to Glycolipid receptors include

• E. Coli, Streptococcus pneumoniae, and Neisseria Gonorrhoenae,

• the Causative agents of urinary tract infectons, pneumonia, and gonorrhea, respectively.

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SPHINGOLIPID STORAGE DISEASES

• Each Lysosomal storage disease is caused by a hereditary deficiency of an enzyme required for the degradation of a specific metabolite.

• Several Lysosomal storage diseases are associated with Sphingolipid metabolism.

• Most of these diseases, also referred to as the Sphingolipidoses, are fatal.

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Tay-Sachs disease

• The most common Sphingolipid storage disease

• is caused by a deficiency of β-hexosaminidase A, the enzyme that degrades the ganglioside GM2.

• As cells accumulate this molecule, they swell up

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Tay-Sachs disease• blindness, muscle weakness,

seizures, and mental retardation) usually appear several months after birth.

• Because there is no therapy for Tay-Sachs disease or for any other of the sphingolipidoses the condition is always fatal (usually by age 3)

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Other SPHINGOLIPID STORAGE DISEASES

• Niemann-Pick disease– Sphingomyleinase deficiency– Liver & spleen filled with lipids,

enlarged– Neurodegeneration

• Gaucher disease• Fabry disease• GM1 Gangliosidosis

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DERIVED, PRECURSOR or ASSOCITED LIPIDS

SteriodsEicosanoidesLipoproteins

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Steroids • are complex derivatives of Triterpenes. • They are found in all eukaryotes and a

small number of bacteria. • Each type of steroid is composed of

four fused rings.• Perhydrocyclopantanophenanthrene• Steroids are distinguished from each

other by the placement of carbon-carbon double bonds and various constituents

• Cholesterol important example

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Cholesterol CH3 CH2 CH2 CH3

CH CH2 CH CH3

C D

A B HO

CH3

CH31234 5

67

89

27

10

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Cholesterol• Cholesterol possesses a branched hydrocarbon side chain at C-17.• hydroxyl group attached to C-3), it is

classified as a sterol. • is usually stored in cell as a fatty

acid Eester.• Abundant in adrenal glands nervous

system• 140 gm in normal adult

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Cholesterol•Normal blood level 150 -200 mg / dl•200 mg / dl is taken

as maximum desirable upper limit

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Cholesteryl ester CH3 CH2 CH2 CH3

CH CH2 CH CH3

C D

A B Fattyacid-O

CH3

CH31234 5

10

67

89

27

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• This esterification reaction is catalyzed by the enzyme

Acyl-CoA:Cholesterol acyl Transferase

(ACAT), located on the cytoplasmic face of the endoplasmic reticulum.

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Cholesterol (function)

1. Stability of phospholipid bilayers (membranes)without affecting fluidity2. Precursor of bile salts (lipid digestion

& absorption)3. Precursor of all steroid hormones4. Precursor of Vitamin D (7 dehydrocholestrol) 3. Precursor of Cardiac glycosides

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Cardiac glycosides• Molecules that increase the force of

cardiac muscle contraction, are among the most interesting steroid derivatives.

• Glycosides are carbohydrate-containing acetals. Although several cardiac glycosides are extremely toxic e.g., ouabain, others have valuable medicinal properties.

• For example, Digitalis, an extract of the dried leaves of Digitalis purpurea is a time-honored stimulator of Cardiac muscle contracton.

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Digitoxin• Digitoxin, the major “cardiotonic”

glycoside in digitalis, is used to treat congestive heart failure (an illness in which the heart is so damaged by disease processe that pumping is impaired).

• In higher than therapeutic doses, Digitoxin is extremely toxic.

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Lipoprotein

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Lipoprotein• Group of molecules transporting lipids in

the bloodstream from one organ to another

• Composition – Triacylglycerols– Phospholipids– Cholesterol– Proteins

• Lipoproteins also contain several types of lipid-soluble vitamins (α-tocopherol and several carotenoids).

• The protein components are called apolipoprotiens or apoproteins.

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Plasma Lipoprotein

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Types of lipoproteins• Lipoprotiens are classified

(named) according to their

1. Density2. Electrophoretic mobility

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DensityThere are six lipoproteins

1. Chylomicrons 2. Chylomicron remnants 3. VLDL 4. VLDL remnants or IDL 5. LDL and 6. HDL.

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Electrophoretic mobility• Chylomicron• lipoproteins• Pre lipoproteins• lipoproteins

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0%

20%

40%

60%

80%

100%

Chylo-microns

VLDL LDL HDL

Lipoprotein Type

Com

posi

tion

C

P

T

C

P

T

T

P

C

C P

T

Figure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).

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Chylomicron

TAG

85%

Ph.lipid 9%

cholesterol 1%

Ch. E

sters 3%P

rotein 2% TAGPh.lipidProteinCh. esterscholesterol othersApo C-II

Apo B-48Apo E

132

Chylomicrons

• are large lipoproteins • of extremely low density• transport dietary Triacylglycerols

and Cholesteryl esters from the intestine to muscle and adipose tissues.

133

Very Low Density Lipoproteins

TAG

50%

Ph.lipid18%

others3%

cholesterol 7%C

h. esters12%

Protein10%

TAGPh.lipidProteinCh. esterscholesterol others

Apo C-IIApo B-100Apo E

134

Very low density lipoproteins (VLDL)• 0.95-1.006 g/cm3• Synthesized in the liver• Transport lipids to tissues. • As VLDL are transported through the body

they become depleted of Triacylglycerols, some Apoproteins & Phospholipids

• The Tricylglycerol-depleted VLDL remnants are either picked up by the Liver or converted to low-density lipoproteins

135

Low density Lipoproteins

Protein24%

Ch. esters

38%

cholesterol 8%

Ph.lipid20%

TAG

10%


Apo B-100

136

Low-density lipoproteins (LDL)• (1.006-1.063 g/cm3)• LDL carry Cholesterol to tissues• In a complex process, LDL are

engulfed by cells after binding to LDL receptors.

• elucidated by Michael Brown and Joseph Goldstein recipients of the 1985 Nobel prize

137

HDL High Density Lipoproteins

TAG

4%

Ph.lipid24%

cholesterol 2%

Ch. esters15%

Protein55%


Apo C-IIApo EApo A

138

High-density lipoprotein (HDL)• 1.063-1.210 g/cm3• also produced in the liver• appears to be the scavenging of

excessive cholesterol from cell membranes.

139

Scavenger role of HDL• Cholesteryl esters are formed when the

plasma enzyme lecithin: cholesterol acyltransferase (LCAT) transfers a fatty acid residue from lecithin to cholesterol.

• It is now believed that HDL transports these cholesteryl esters to the liver.

• Liver, the only organ that can dispose of excess cholesterol, converts most of it is to bile acids.

140

Lipids And Atherosclerosis

141

ATHEROSCLEROSIS:• Atherosclerosis is a chronic disease in

which soft masses, called Atheromas (plaque), accumulate on the inside of arteries

• is a progressive process, smooth muscle cells, macrophages, and various cell debris build up.

• macrophages fill with lipid (predominantly Cholesterol and Cholesrteryl esters derived from LDL), take a foam like appearance, Foam cells.

• deposits mechanically damaged artery wall

142

• Eventually, atherosclerotic plaque may calcify and protrude sufficiently into arterial lumens. the blood flow is impeded.

• Disruption of vital organ functions, especially those of the brain, heart, and lungs caused by oxygen and nutrient deprivation

• In coronary artery disease, one of the most common consequences of atherosclerosis, this deprivation damages heart muscle

143

Plasma LDL & HDL• Because most of the cholesterol

found in plaque is obtained by the ingestion of LDL by foam cells, high plasma LDL levels are directly related with high risk for coronary artery disease.

(LDL have a high cholesterol and cholesteryl ester content)

145

Plasma LDL & HDL• In contrast, a high plasma HDL level is

considered to be associated with a low risk for coronary artery disese.

• Liver cells (hepatocytes) are the only cells that possess HDL receptors

• Other high risk factors include – a high-fat diet– Smoking– Stress– sedentary lifestyle

146

• The most important bile acids are 1. Cholic acid2. Chenodeoxycholic acid. Cholesterol is precursor of bile salts In liver Required for lipid digestion & absorption

BILE ACIDS AND SALTS

147

ketone bodies• There are three compounds

grouped under the term ketone bodies; these are

• Acetoacetic acid- Hydroxybutyric acid• Acetone

149

EICOSANOIDS

150

EICOSANOIDS• Compounds derived from 20 C

polyunsaturared fattyacid Arachidonic acid

• 20:4 (5, 8, 11, 14)• Linoleic acid is dietery precurssor,

elongated & desaturated in body to Arachidonic acid

• Arachidonic acid is stored in the membranes as Phosphatidylionositol

151

EicosanoidsInclude• Prostaglandins (PG)• Thromboxanes (TX)• Leukotrienes (LT)• Prostacyclins

152

Salient features• Hormone like action But• Produced in small amount • By almost all tissues• Act locally• Extremly short half life, not stored • Performing variable function in different

tissues depending upon receptor they bind with

• Responses are physiologic as well as pathologic

153

Structures of a few different arachidonic acid derivatives

155

In general: regulate local inflammation but each molecule has specific effects

eg. Prostaglandin E2 - vasodilator Prostaglandin F2 - vasoconstriction Prostacyclin (PGI2) - vasodilator / inhibits

platelet aggregation Thromboxane A2 - vasoconstrictor /

stimulates platelet aggregation

Different prostaglandins are made by different cell types.

eg. Thromboxane A2 is made in platelets Prostacyclin is produced by vascular

endothelial cells

156

Functions (examples) TXA2 in Platelets • aggregation of Platelets• Vasoconstriction• Contraction of smooth musclesPGl2 in endothelium• Vasodilation• Inhibition of aggregation of PlateletsOpposing action limits Thrombi

formation------- Al-Mizan

157

PGF2 most tissues• Vasoconstriction• Contraction of smooth muscles• Contraction of uterine musclesPGE2 most tissues• Vasodilation• Relaxation of smooth muscles• Used to induce labour ,Contraction

of uterine muscles

158

Chemistry of Lipids

159

Role of Eicosanoids• Mediating inflammation• Fever• Allergic response• Gastric integrity• Renal function• Ovarian & uterine function• Bone metabolism• Nerve & brain • Smooth muscle regulation• Platelets homeostasis

160

Eicosanoids & disease• Inflammation Vasodilatation & capillary

permeability edema & pain Glucocorticoids used as Anti-

Inflammatory & Anti allergicReason they inhibit Phospholipase A

pathway of Eicosanoids synthesis

161

Aspirin & Eicosanoids • Inhibits fever & pain • In low doses prevents Myocardial

infarction• Reason it irreversibly inhibits synthesis of

Prostacylins & TXA2 so incidence of Thrombo-embolism

162

• Type 2 Diabetic patients show in insulin secretion due to PGE2

• Peptic ulcer, PGE2 analogues HCl secretion

• Indomethazine drug tried in patent Ductus Arteriosis. It inhibits the PG synthesis ( secretion stops closure)

163

• Bronchial asthma Antigen/Antibody recation liberates

several Eicosanoids cause intense reaction with Bronchoconstriction & Broncho-odema

164

Lipid peroxidation &Its significance

165

Lipid peroxidation• It is auto-oxidation when lipids are

exposed to oxygen• Responsible for “ rancidity ” of fats• Rancidity is deterioration in fat

foods & development of specific odour, color, taste

166

Peroxidation in the body• In vivo, it causes damage• Free radicals are produced during

peroxide formation from naturally occurring polyunsaturated fatty acids

• It is a chain reaction

167

Same • Free radicals• Superoxides• Reactive oxygen species (ROS)• Respiratory Burst• Oxidative stress

168

Peroxidation in the body• Partial reduction of molecular Oxygen• O2 diffuses rapidly in to & out of cells

because it is soluble in non-polar lipid core of membrane

• It can accept single electron to form unstable derivative.– H2O2 Superoxide radical– OH- Hydroxyl Radical– O- single oxygen.

169

• Dangerous to cell if formed in significant amount.

• Antioxidant mechanism are the agents to trap it, in organism to keep it at minimum level– Antioxidant enzymes & coenzymes

system e.g Glutathione, Catalase, NADPH[(nicotinamide adenine dinucleotide phosphate-oxidase]

– Antioxidant vitamins, A, C, E

Antioxidant mechanism

170

Action of Glutathione 2 R-SH + H2O2 R-S-S-R + 2H2O 2 Glutathione-SH + H2O2

G Peroxidase G reductase

+NADPH+H+ G-S-S-G + 2H2O

171

• Enzyme inactivation.• Depolymerization of CHO• Depolymerization of DNA• Membrane destruction

Oxidative stress can result in

172

Respiratory Burst• Cells like macrophages, produce

large number of Free radicals, to kill the bacteria & damaged cells

• Rapid consumption of molecular Oxygen that accompanies formation of Superoxides is called

Respiratory BurstRespiratory Burst

173

Causes of Oxidative stress ( peroxidation)

• Metabolic abnormalities • Overuse of some drugs, Alcohol• Radiation• Repeated contact with

environmental contaminations e.g Tobacco smoke

• ↓ level of Antioxidants

174

• in addition to aging process, Oxidative stress linked to 100

human diseases, examples • Cancer • CVS disorders[Cyclic vomiting syndrome]

– Atherosclerosis – Myocardial Infarction– Hypertension

• Neorologial disorders– Parkinson syndrome– Alzheimer’s disease

lipid chemistry

Health & Medicine