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number 25

Done by موسى صبح

Corrected by عبد الرحمن الحنبلي

Doctor فيصل الخطيب

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Introduction

The subject of this lecture is glycerophospholipids also known as phosphoglyceridesor

phosphoacylglycerols, the sheet will talk about (structure, degradation, synthesis, remodeling and

functions) ofphosphoacylglycerols, feel free to refer to the doctor’s slides andlippincot chapter 17 for

more information.

Structure of glycerophospholipids

As the name implies, the general structure of phosphoacylglycerol shows glycerol, 2 fatty acids, a

phosphate group and alcohol,these are the components of phosphoacylglycerol. So 5 different

componentsare connected together by4 ester bonds :-

- 2 ester bonds between glycerol and fatty acids.

- 1 ester bond between glycerol and phosphate.

- 1 ester bond between phosphate and alcohol.

*phosphate can form 2 ester bonds (diester bond).

The parent compound of phosphoacylglycerol is known as phosphatidic acid (glycerol, 2 fatty acids and

phosphate), phosphatidate is the ionized form of phosphatidic acid.

There are 5 alcohols that bond with phosphatidic acid by ester bond to form the phosphoacylglycerol,

we can classify them into two groups:-

1- Alcohols (inositol, glycerol)

*Notice that inositol or myo-inositol is a six membered ring with six hydroxyl groups, it is not a

sugar, it is an alcohol (refer to slide 4 for the structure)

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2- Aminoalcohols: all of these alcohols end up with “ine” which indicates that they have amino

group (ethanolamine, serine, choline).

*we will study the structure of these molecules to understand their properties

*this is not the way to produce them

*ethanolamine is our reference in comparing between these molecules

*see the figure below

Ethanol – ethanolamine

If we replace one hydrogen from ethanol by amino group we will get ethanolamine

*ethanol doesn’t convert into ethanolamine in our bodies, this is just to understand the

relationship between the two molecules.

Ethanolamine – serine

If we replace one hydrogen from ethanolamine with carboxyl group (COO-), ethanolamine

will be called serine.

*serine is a common amino acid.

Ethanolamine – choline

Choline is obtained by replacing three hydrogens from ethanolamine with three methyl

groups (CH3).

*When phosphatidic acid form ester bond with an alcohol the ending “ic” becomes “yl”, for example;

phosphatidyl serine, phosphatidyl inositol…

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phosphatidyl choline

Commonly known as lecithin, you can find it in powdered milk or in chocolate bars.

Usually when biochemists want to study a molecule and its properties they make a space filling

modelthat represent it.

Space filling model:usage of small spheres that represents atoms (carbon, hydrogen, oxygen,

nitrogen…etc.) to build a structure of a molecule.

Figure 11-6 below is the space filling model of phosphatidyl choline, from the structure we can conclude

that this molecule has two regions :-

- Hydrophobic/non polar (fatty acids/tails): cannot dissolve in water, hydrophobic molecules will

disrupt the hydrogen bonds in water, so it is more comfortable for the water to exclude them.

- Hydrophilic/polar (head/choline):the head is negatively charged (oxygen) and positively charged

(nitrogen) so it can interact with water .

* Thekink/angle in the fatty acid indicates the presence of the double bond in the cis configuration.

Because of the hydrophobic (tail) region and the hydrophilic (head) region, when we try to dissolve

phosphatidyl choline in water, large number of these molecules aggregate together in a non polar

interactions where the head is on the exterior side and the tails on the interior side. These aggregations

are calledmicelles. By forming micellesphosphatidyl choline can dissolve in water.

*Phospholipids form cells' membranes (phospholipid bilayer) and can also form liposomes which have

aqueous cavity inside.

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Application (property of forming micelles)

As we all know, oil cannot dissolve in water, instead, it forms distinct layer above the water surface. But

when phospholipids are added into the mixture, they will form micelles and integrate the nonpolar oil

molecules into the interior of the micelles,this process is called emulsification, allows us to dissolve oils,

butters and fatty acids in water, The resulted solution is a suspension which has a milky appearance

(micelles reflect light) which is called emulsion, and phospholipids are called emulsifiers.

So now we can understand why phosphatidyl choline (lecithin) is added to powdered milk and chocolate

bars, it acts as emulsifier.

Phosphatidyl alcohol structure

Phosphatidyl ethanolamine

Phosphatidyl serine

Phosphatidylinositol, Even if there is no amine group (positive charge) the head is polar (because of the hydroxyl groups. This implies also on phosphatidylglecerol

*our cells’ membranes are made of phospholipids, all of these phospholipids can be found in the plasma

membrane in a different ratio or concentrations.

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Degradation of phospholipids

All of the phospholipids have 4 ester bonds, they can be hydrolyzed to form alcohol and carboxylic acid,

this process requires enzymes, each ester bond requires a different enzyme, these enzymes are known

as phospholipases.

- Phospholipase A1: hydrolyze the 1stester bond (between glycerol and fatty acid 1).

- Phospholipase A2: hydrolyze the 2ndester bond (between glycerol and fatty acid 2).

- Phospholipase C: hydrolyze the ester bond between glycerol and phosphate.

- Phospholipase D: hydrolyze the ester bond between alcohol and phosphate.

All of these phospholipases work on intact molecules, they don’t work sequentially, for example

phospholipase A2doesn’t work after phospholipase A1.each one will work on an intact molecule (have 4

ester bonds).

What about phospholipase B? Suppose that the first fatty acid is removed, here comes the work of phospholipase B, so phospholipase

B work after phospholipase A (A1 or A2), it acts on lysophosphoglycerol (phosphoacylglycerol without

one fatty acid) and remove the remaining fatty acid.

For example; phospholipase B acts on lysophosphatidylcholine, it is the product of hydrolyzing the

second ester bond between glycerol and the second fatty acid by phospholipase A2.

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Pieces of information about phospholipases

- Phospholipase A2

1. Phospholipase A2 is found in snake and bee venoms, so when a snake bites someone, the

phospholipases act on the phospholipids of the cell’s membranes to produce lysophospholipids,

we call them lysophospholipids because they cause lysis of cells. So they have strong detergent

actions (like very strong soap) and they cause degradation of tissues.

2. Phospholipase A2 act on phosphatidylinositol to release arachidonic acid and it isused as a

precursor for synthesis of prostaglandins, so if the cell is going to produce prostaglandins

phospholipase A2 act on phosphatidylinositol production of arachidonic acid production of

prostaglandins.

3. Phospholipase A2 is inhibited by glucocorticoids

- Phospholipase C: found in the membrane and it causes the release of diacylglycerol and

inositol triphosphate

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Biosynthesis of phosphoacylglycerol

We consider the following to understand the synthesis process :-

- Glycerol esterified to two fatty acids is diacylglycerol, diacylglycerol is alcohol1.

- Glycerol, serine, choline…arealcohol2.

- Phosphate group is one of the components.

So we have three components (alcohol1, phosphate and alcohol2) and we want to join them together,

how they can be joined?

1. Adding phosphate group to alcohol1 (diacylglycerol) and this is easily done by using ATP. By the

end of this step we will have phosphorylated alcohol1 (phosphoalcohol1).

*alcohol2 can also be phosphorylated/activated.

2. Transferring the phosphorylated/activated alcohol to the other alcohol.We use activated

carriers in this step , it can be done by two ways :-

- Transferring phosphorylated alcohol1 to alcohol2

- Transferring phosphorylated alcohol2 to alcohol1

Production of activated carrier (carrier of activated/phosphorylated alcohol)

CTP + phosphorylated alcohol CDP-alcohol + PPi

CTP: cytosine ribose triphosphate

PPi: pyrophosphate

This is a transfer reaction where two phosphates on CTP are replaced by phosphorylated alcohol, so we

end up with pyrophosphate and CDP-alcohol.

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ΔG of the reaction is almost zero because it includes the breaking of a high energy bond "P-P in CTP",

and the formation of a high energy bond "P-P in the CDP-alcohol". Pyrophosphate is hydrolyzed to

inorganic phosphates as soon as it is produced, the rapid removal of pyrophosphate will make ΔG of this

reaction negative (shift it toward the forward direction).

Synthesis of phosphatidylinositol (example on first way of transferring)

Transfer of phosphorylated alcohol1/phosphatidic acid to alcohol2/inositol and we will end up with CMP

and phosphatidyl inositol.

CDP-diacylglycerol + inositol Phosphatidyl inositol +CMP

Synthesis of phosphatidyl choline (example on the second way of transferring)

Transferring of phosphocholine (active form of choline) to diacylglycerol, this reaction will produce CMP

and phosphatidyl choline.

CDP-choline + diacylglycerol phosphatidyl choline +CMP

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Alteration of polar head group

Alteration of polar head group means exchange of the polar head group

Phosphatidyl serine synthesis

Phosphatidyl serine is produced by exchanging ethanolamine with serine, and we will end up

havingphosphatidyl serine and ethanolamine, we don’t have CDP-serine.

Also this is how ethanolamine is produced, we can use it again by phosphorylating it and make

phosphatidyl ethanolamine again.

The first phosphatidyl ethanolamine is produced from decarboxylation of phosphatidyl serine, so

another way to produce phosphatidyl ethanolamine is by decarboxylation of phosphatidyl serine.

Methylation of phosphatidyl ethanolamine

We can make phosphatidyl choline from methylation of phosphatidyl ethanolamine. Methylation means

theaddition of methyl groups, the source of methyl groups in this reaction is S-adenosyl methionine

(SAM).

So we need 3 methyl groups (produced from 3 SAM) to convert phosphatidylethanoleamine into

phosphatidylcholine .

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S-Adenosyl methionine: it is methionine (sulfur containing amino acid) joined to adenosine, it is the

methyl donor in this reaction and many other reactions, because it can let go of methyl group very

easily, what makes it an excellent methyl donor is the sulfur in the methionine, it binds three atoms

which is unusual (sulfur usually can form two covalent bonds), the third bond is formed with adenosine

to make SAM, so this makes it easy to lose CH3 in a methylation reaction.

When S-Adenosyl methionine (SAM)loses CH3, it becomes S-adenosyl homocysteine which isthe same

as cysteine but it has anextra CH2.

Remodeling of phospholipids (changing the fatty acids)

- If we have lysophosphatidyl choline (less by 1 fatty acid compared to phosphatidyl choline), when

the fatty acid is removed by the action of phospholipase A2 on phosphatidyl choline, we can replace

it by Arachidonic acid in the form of arachidonyl CoA, so we will have phosphatidyl choline again.

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- Ether glycerophospholipids : fatty acid connected with glycerol on carbon 1 by ether bond instead

of an ester bond.

Platelet activating factor is an ether glycerophospholipids, carbon 2 in glycerol is connected with

acetic acid instead of long chain fatty acid, so phospholipids function as signal molecules and also as

precursors of signal molecules. (The function of platelet activating factor is aggregation of platelets)

Surfactant action of phospholipids

Surfactant is a substance that lowers the surface tension.

Surface tension results from hydrogen bonds between water molecules, each water molecule can form

4 hydrogen bonds therefore large number of hydrogen bonds makes the water droplet has its spherical

shape (dome like shape on a glass surface for example) where as other substances like oil or acetone will

not form the droplet shape and they will spread, surface tension is a property of water.

Surfactants are important in the lung. The smallest unit of the lung is the alveolus. At the end of

respiration, alveoli are fully expanded. During expiration, the presence of surfactants allows the alveolus

to remain partially deflated. Because of the presence of surfactants, water on the surface of the alveolus

spreads and prevents the collapse of the alveolus. If the alveolus lacks surfactants (due to insufficiency

in production or secretion), it will collapse.

So surfactant action of phospholipids is important for the function of the lung, our lung contain

phospholipids to reduce the surface tension in the alveolus.

The synthesis of phospholipids in the lungs starts during the fetal life after the 38th week of gestation, if

the baby is born before that (7th or 8th month) he will suffer from respiratory destresssyndrome (RDS).If

the physician expects that the pregnant woman will deliver preterm/premature, they will inject her with

something (glucocorticoids by the book, not mentioned by the doctor) that stimulate or accelerate the

production of surfactants, so that when the baby is born he will not have any problems in breathing.

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Functions of phosphoacylglycerols (summary)

1- Cell membranes

2- Source of arachidonic acid

3- Signaling molecules: platelet-activating factor is an important signaling molecule for platelets

activation and aggregation.

4- Used as emulsifiers.

5- Surfactant action of phospholipids is important for the function of the lung.

“Human potential for evolution is limitless”

“You should enjoy the little detours to the fullest. Because that’s where you’ll find things more

important than what you want”