Chemistry of LipidsPHOSPHOLIPIDS Part – 2

V.S.RAVI KIRAN

V.S.RAVIKIRAN, MSc., Department of Biochemistry,

ASRAM Medical college, Eluru-534005.AP, India.vsravikiran2013@gmail.c

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PHOSPHOLIPIDS• They contain glycerol, fatty acids and a nitrogenous base.

• Lecithin, was discovered in 1870 by the German biochemist Ernst

Hoppe- Selyer.

• Strecker characterized choline in 1861.

• In 1884, Thudichum JLW described sphingosine, sphingomyelin,

cerebrosides, cephalin and lecithin in brain tissue.

Phosphatidates• These are derivatives of phosphatidic acid, which is the simplest

phospholipid.

• Phosphatidic acid is made up of one glycerol to which two fatty acid

residues are esterified to carbon atoms 1 and 2. The 3rd hydroxyl

group is esterified to a phosphoric acid.

L-Phosphatidic acid

Phosphatidates

• The molecule has an asymmetric carbon atom and therefore, exhibits

optical isomerism.

• L-isomer is found in nature.

Amphipathic Nature

• Phospholipids in general are amphipathic, particularly Lecithin.

• They have both hydrophobic and hydrophilic portion in their

molecule.

Amphipathic NaturePhospholipids form the bilayer

Amphipathic NaturePhospholipids form micelles and liposomes

Amphipathic Nature

• The glycerol along with the phosphoric acid and choline constitute the

polar ‘head' of a phospholipid molecule, whereas the hydrocarbon

chains of the fatty acids represent the nonpolar ‘tail'.

Micellar Formation• When phospholipids are distributed in water, their hydrophobic parts

keep away from water, forming molecular aggregates called micelle.Phospholipids form micelles and liposomes

Micellar Formation

• These are involved in solubilization of lipids in aqueous media and

help in digestion and absorption of lipids.

Liposomes• A lipid bilayer will close on itself under appropriate conditions to form

liposomes. Unilamellar or multilamellar liposomes may be formed.

They may be prepared by sonication of mixtures of phospholipids and

cholesterol.

Phospholipids form micelles and liposomes

Liposomes

• Liposomes are microscopic spherical vesicles.

• When mixed in water under special conditions, the phospholipids

arrange themselves to form a bilayer membrane which encloses some

of the water in a phospholipid sphere.

Liposomes

• Drugs, proteins, enzymes, genes, etc. may be encapsulated by the

liposomes which could act as carriers for these substances to target

organs.

• Liposome-entrapped drugs exhibit superior pharmacological

properties than those observed with conventional formulations.

Liposomes• Liposomes have important applications in -

cancer chemotherapy,

antimicrobial therapy,

gene therapy,

vaccines and diagnostic imaging.

Aquasomes

• They are one of the most recently developed delivery systems that

are making a niche as the peptide/protein carriers.

• These are nano particulate carrier systems with three layered self-

assembled structures

Aquasomes• They comprise the central solid nanocrystalline core coated with

polyhydroxy oligomers onto which biochemically active molecules are

adsorbed.

• The solid core provides the structural stability.

• The carbohydrate coating stabilizes the biochemically active molecules.

• As the conformational integrity of bioactive molecules is maintained,

aquasomes are being proposed as a carrier system for delivery of

peptide based pharmaceuticals.

Aquasomes

• The delivery system has been successfully utilized for the delivery of

insulin, hemoglobin and various antigens.

• Oral delivery of enzymes like serratiopeptidase has also been

achieved.

Biomembranes• The molecules align themselves to form monolayers with the polar

heads pointing in one direction and the nonpolar tails in the opposite

direction.Phospholipids form the bilayer

BiomembranesPhospholipids form micelles and liposomes

Biomembranes

• Only fatty acids with more than 6 carbon atoms form monolayers.

This explains their role as components of biomembranes.

• The self-assembly of phospholipids into bilayers is driven by

hydrophobic interaction.

Biomembranes

• They also act as detergents and emulsifying agents.

• In vivo, they act as pulmonary surfactants.

Phosphatidylcholine or Lecithin

• This is a nitrogen containing phospholipid.

• The word lecithin is derived from the Greek word, lekithos = egg yolk.

• It contains glycerol.

Phosphatidylcholine or Lecithin

• The alpha and beta positions are esterified with fatty acids.

• Usually, the fatty acid attached to the betacarbon, is a PUFA molecule.

Phosphatidylcholine or Lecithin

Lecithin R1 and R2 are fatty acids. Red rectangle depictsglycerol group. The blue rectangle is choline which shows polar or hydrophilic property

Phosphatidylcholine or Lecithin• The phosphoric acid is added to the third position, to form

hosphatidic acid. The phosphate group is esterified to the quaternary

nitrogen base, Choline.

Lecithin R1 and R2 are fatty acids. Red rectangle depictsglycerol group. The blue rectangle is choline which shows polaror hydrophilic property

Phosphatidylcholine or Lecithin• The molecules of lecithin exist as zwitterions (pl = 6.7).

Action of Phospholipases• Phospholipases are enzymes that hydrolyze phospholipids. Different

phospholipases are involved in the hydrolysis of specific bonds in

lecithin

Action of Phospholipases• Phospholipase A2 acts on an intact lecithin molecule hydrolyzing the

fatty acid esterified to the beta (second) carbon atom.

• The products are Lysolecithin and fatty acid.

• Lysolecithin is a detergent and hemolytic agent.

• The enzyme is present in the venom of viper snakes.

• The hemolysis and consequent renal failure seen in viper poisoning

could be thus explained.

Action of Phospholipases• Actions of other phospholipases are shown in Figure.

The products formed in each case may be summarized as follows:

Phospholipase A2 Lecithin Lysolecithin + fatty acid Phospholipase A1 Lecithin 1 Acyl glycerophosphorylcholine +

fatty acid Phospholipase C Lecithin 1,2 diacylglycerol + Phosphoryl

choline Phospholipase D Lecithin Phosphatidic acid + choline

Lung Surfactants

• Normal lung function depends on a constant supply of lung

surfactants.

• It is produced by epithelial cells.

• It decreases surface tension of the aqueous layer of lung and prevents

collapse of lung alveoli.

Lung Surfactants

• Constituents of surfactants are dipalmitoyl lecithin, phosphatidyl

glycerol, cholesterol and surfactant proteins A, B and C.

• During fetal life, the lung synthesizes sphingomyelin before 28th week

of gestation.

• But as fetus matures, more lecithin is synthesized.

Lung Surfactants

• The lecithin-sphingomyelin (LS) ratio of amniotic fluid is an index of

fetal maturity.

• A ratio of 2 indicates full lung maturity.

• Low surfactant level can lead to respiratory distress syndrome (RDS),

which is a common cause of neonatal morbidity

Respiratory Distress Syndrome (RDS)

• It is due to a defect in the biosynthesis of dipalmitoyl lecithin (DPL),

the main pulmonary surfactant.

• Premature infants have a higher incidence of RDS because the

immature lungs do not synthesize enough DPL.

Phosphatidylethanolamine or Cephalin

• Cephalin differs from lecithin in that the nitrogen base ethanolamine

is present instead of choline. Cephalin is also found in biomembranes

and possesses amphipathic properties.

Cephalin (Phosphatidylethanolamine)

Phosphatidylinositol• Here, phosphatidic acid is esterified to inositol. Phosphatidyl inositol

bisphosphate or PIP2 is present in biomembranes.

• This compound plays a vital role in the mediation of hormone action

on biomembranes and acts as a second messenger.

Phosphatidylinositol

Plasmalogens

• These are phospholipids which have an aliphatic long chain α-β

unsaturated alcohol in ether linkage with the first hydroxyl group of

glycerol.

Ethanolamine plasmalogen

Plasmalogens

• The second OH group is esterified to a fatty acid.

• The phosphoric acid is attached to choline or ethanolamine.

Ethanolamine plasmalogen

Plasmalogens

• The alcohols have about C12 to C18 chain length.

• Plasmalogens are found in biomembranes in brain and muscle.

Ethanolamine plasmalogen

Phosphatidylglycerol

• It is formed by esterification of phosphatidic acid to glycerol.

• When two molecules of phosphatidic acid are linked with a molecule

of glycerol, diphosphatidylglycerol or cardiolipin is formed.

Phosphatidylglycerol• It is the major lipid of mitochondrial membrane. Commercially, it is

extracted from myocardium.

• Decreased cardiolipin level leads to mitochondrial dysfunction, and is

accounted for-

• Heart failure,

• hypothyroidism and

• some types of myopathies.

Sphingolipids

• The sphingosine containing lipids may be of 3 types;

• phosphosphingosides,

• glycosphingolipids and

• sulfatides.

Sphingolipids

• All sphingolipids have the long aliphatic amino alcohol sphingosine

which is attached to a fatty acid in amide linkage to form a ceramide.

• The fatty acid has a chain length varying from C18 to C24.

Sphingosine

Sphingolipids• All sphingolipids have the long aliphatic amino alcohol sphingosine

which is attached to a fatty acid in amide linkage to form a ceramide.

• The fatty acid has a chain length varying from C18 to C24.

Ceramide

Phosphosphingosides• They contain phosphoric acid group.

• A common phosphosphingoside present abundantly in

biomembranes, especially of the nervous system, is sphingomyelin. It

contains choline.

Sphingomyelin

Sphingomyelins

• Sphingomyelins are the only sphingolipid that contain phosphate

and have no sugar moiety.• They are found in large quantities in nervous system.

Sphingomyelins• They are found in large quantities in nervous system.

• Different sphingomyelins may be formed depending on the fatty acid

attached.

• Common fatty acids found are—

• lignoceric (24 C),

• nervonic (24 C, one double bond) and

• cervonic (22 C, 6 double bonds) acids.

Sphingomyelins

• Because of its amphipathic nature sphingomyelin can act as an

emulsifying agent and detergent.

• The relative proportion of lecithin and sphingomyelin is important in

biological fluids like bile, amniotic fluid, etc.

• Sphingomyelin combined with fatty acid is called ceramide, which is a

component of glycosphingolipids.

Clinical relevance of antiphospholipid antibody is

described in Box.

Non-phosphorylated Lipids

• Glycosphingolipids (Glycolipids)

• They are seen widely in nervous tissues. This group of lipids do not

contain phosphoric acid; instead they contain carbohydrates and

ceramide.

• Ceramide + Glucose → Glucocerebroside

• Ceramide + Galactose → Galactocerebroside

Globosides (Ceramide Oligosaccharides)

• They contain two or more hexoses or hexosamines, attached to a

ceramide molecule.

• Ceramide + Galactose + Glucose → Lactosyl ceramide

• Lactosyl ceramide is a component of erythrocyte membrane.

Gangliosides

• They are formed when ceramide oligosaccharides have at least one

molecule of NANA (N-acetyl neuraminic acid) (sialic acid) attached to

them.

• Ceramide—Glucose—galactose—NANA;

• This is designated as GM3 (ganglioside M3).

Gangliosides

• Gangliosides contribute to stability of paranodal junctions and ion

channel clusters in myelinated nerve fibers.

• Autoantibodies to GM1 disrupt lipid rafts, paranodal or nodal

structures, and ion channel clusters in peripheral motor nerves.

Sulfolipids or Sulfatides

• These are formed when sulfate groups are attached to ceramide

oligosaccharides.

• All these complex lipids are important components of membranes of

nervous tissue.

Sulfolipids or Sulfatides

• Failure of degradation of these compounds results in accumulation of

these complex lipids in CNS.

• This group of inborn errors is known as lipid storage diseases.

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