Dr. M.

Azhar Chishti
Dept. Medical Biochemistry
 Lecture Objective
1. To study the structure of physiologically important
phospholipid classes- glycerophospholipids and sphingolipids.
 
2. To discuss the synthesis of phospholipids of clinical and
physiological relevance and their degradation by
phospholipases.

3. To study the role of phospholipids like phosphatidylinositol

in signal transduction and membrane anchoring choline,
ethanolamine  and serine, cardiolipin and sphingomyelin etc.
 Lecture Outline
1. Overview of phospholipids.

2. Structure of Glycerophospholipids and sphingolipids.

3. Synthesis of phospholipids: Phosphatidic acid,

phosphatidyl-choline, ethanolamine   and serine, cardiolipin
and sphingomyelin etc.

4. Degradation of phospholipids by phosphalipases.

5. Role of phosphatidyl choline in lung surfactant

6. Role of phsophatidylinositol in signal transduction and

membrane anchoring .
 Phospholipid
 Polar compounds composed of alcohol attached by a ‫مربوط بــــ‬
‫راـبطهـ‬phosphodiester bridge to either diacylglycerol or
sphingosine.

 Amphipathic ) ‫ متردد ( محبوكارهـ لــلماء‬in nature, has a hydrophilic

head (phosphate + alcohol eg., serine, ethanolamine, and choline) and
a long, hydrophobic tail (fatty acids or derivatives ).

 In membranes, the hydrophobic portion is associated with the

nonpolar portions such as glycolipids, proteins, and cholesterol.

 The hydrohilic polar head extends outward, facing intracellular

or extracellular aqueous environment (see Figure).
‫االسماء تشرح في‬
‫شريحه ‪7‬‬
  Membrane phospholipids also function as : 1- a reservoir ‫ حـافظ‬for
intracellular messengers, and, 2-for some proteins, phospholipids
serve as anchors )‫ مرساهـ ( مثبت‬to cell membranes.

 Non-membrane-bound phospholipids‫اــلفـوسفـولبدز اــلذيل ـمـ يــدخلفـــي‬

‫ تـــركيباــلجدر اــلخلويهـ ( حـر ) ل ـهـ وظيفهـ‬: serve additional
functions in the body, for example, 1-as components of lung
surfactant and 2-essential components of bile, where their‫اــلبايلهي‬
‫ اــلمكاناــلذيل ـهـ وظائفتـــنظيف‬detergent properties aid "in the solubilization
of cholesterol.‫مثلاـخراـج اــلكلويسترول‬
 ‫ارتباطات الفسفولبدز‬
‫ بالجليسرول‬: ‫اوال‬
Glycerophospholipids : are formed from phosphatidic acid
(PA) and an alcohol.

Serine + PA - phosphatidylserine (PS)

Ethanolamine + PA - phosphatidylethanolamine (cephalin)

Choline + PA - phosphatidylcholine (lecithin) PC

Inositol + PA - phosphatidylinositol (PI)

Glycerol + PA  phosphatidylglycerol (PG)

 (Cardiolipin) ‫اـسمـ فـــسفولبدز‬
‫يــستخدمـ لــلدالــلهـ علىمرضاــلزهري‬

Two molecules of phosphatidic acid esterified

through phosphate to an additional molecule
of glycerol are called cardiolipin.

This is the only human glycerophospholipid

that is antigenic.

cardiolipin is recognized by antibodies raised

against Treponema the bacterium that causes
syphylis‫اــلزهري‬.

[Cardiolipin is an important component of the

inner mitochondrial membrane
and bacterial membranes.]
 Plasmalogens

When the fatty acid at carbon 1 of a glycerolphospholipid is

replaced by an unsaturated alkyl group attached by an
ether ‫( راـبطهـ اـيثر‬rather than‫ بـــدال من‬by an ester) linkage ‫ مهمهـ‬to the
core glycerol : molecule, a plasmalogen is produced.

Phosphatidalethanolamine is abundant ‫ غنيبــــ‬in nerve tissue is a

plasmalogen.

Phosphatidalcholine (abundant in heart muscle) is the other

quantitatively ‫ كـميهـ‬significant ether lipid in mammals.
 Platelet-activating factor (PAF)

PAF is an unusual ether ‫مرتبط بـــراـبطهـ اـيثر اـيضا‬

glycerophospholipid, with a saturated alkyl group ‫ اـنلــديهـا‬-1‫تـــختلفعناــلليقــبل‬
‫ راـبطهـ مشبعهـ‬in an ether link to carbon 1 and 2>>> ‫اــالختالفاــلثاني‬- an acetyl
residue (rather than a fatty acid) at carbon 2 of the glycerol
backbone.

PAF is synthesized and released by a variety of cell types that

binds to surface receptors, triggering potent‫ قــوي‬thrombotic and
acute inflammatory leads to hypersensitivity & anaphylactic‫ردود فـــعل‬
‫ مناعيهـ‬reactions.

It causes platelets to aggregate and degranulate the neutrophils

and alveolar macrophages to generate superoxide radicals that
killed the bacteria.

PAF is one of the most potent bioactive molecules known,

 ‫ ارتباط الفسفولبدز بالسفينقو‬: ‫ثانيا‬
Sphingophospholipids or sphingomyelin

The backbone of sphingomyelin is the amino alcohol

sphingosine, rather than glycerol.

A long-chain fatty acid is attached to the amino group of

sphingosine through an amide linkage‫اــلليقــبلكـان( اـستر او فـــيبـــعضاــلحاــالت‬
) ‫اـيثر‬, producing a ceramide, which serve as a precursor of glycolipids.

‫ مهمه‬: The alcohol group at carbon 1 of sphingosine is esterified

to phosphorylcholine, producing sphingomyelin, the only
significant sphingophospholipid in humans.

Sphingomyelin is an important componant of the myelin of nerve

fibers (myelin sheath) that insulates and protects neuronal fibers
of the central nervous system.
 Synthesis of Phospholipid

1. Glycerophospholipid (GP) synthesis involves ‫ طرقاــلتصنيعـ تـــتمـ بــــاما‬:

either the1- donation of phosphatidic acid from CDP-diacylglycerol
to an alcohol, or 2- the donation of the phosphomonoester of the
alcohol from CDP-alcohol to 1,2-diacylglycerol. CDP is cytidine
diphosphate.

2. In both cases, the CDP-bound structure is considered an "activated

intermediate," and CMP is released as a side product of GP
synthesis.

3. A key concept in phosphoglyceride synthesis, is activation either of

diacylglycerol or the alcohol
‫تريحك من‬ to be
‫القادمه‬ added
‫الصفحه‬ by linkage
‫الرسمه‬ ‫ انظر‬with CDP.
‫صداع الراس هذا‬
‫الطريقه ‪1‬‬

‫في كل‬
‫الحالتين يتم‬
‫اخراج‬
‫‪CMP‬‬

‫الطريقه ‪2‬‬

‫الفرق بين الطريقتين فقط مكان وجود‬

‫‪CMP‬‬
4. The fatty acids esterifies to the glycerol alcohol groups can vary
widely, contributing to the heterogeneity of this group of compounds.

5. Phospholipids are ‫ مهمهـ‬synthesized in the Smooth ER-- then

transported to Golgi apparatus and then membranes organelles or
plasma membrane, or are secreted by exocytosis‫اــالخراـج اــلخلوي‬.

6. There are two classes of phospholipids: Those have either glycerol as

a backbone or contain sphingosine. ‫كـما شــرح منقــبل‬

7. Both classes are found in membranes and play a role in the

generation of lipid-signaling molecules.
 A. Synthesis of phosphatidic acid (PA)

1. PA is the precursor ‫ اــلمادهـ اــالوليهـ‬of many other

phosphoglycerides. The steps in its synthesis
from glycerol phosphate and two fatty acyl
CoAs were in which PA is shown as a
precursor of triacylglycerol.

2. All cells except mature erythrocytes can

synthesize phospholipids, whereas
triacylglycerol synthesis occurs only in liver,
adipose tissue, lactating mammary glands, and
intestinal mucosal cells.
 B: Synthesis of phosphatidylethanolamine (PE) &
phosphatidylcholine (PC)

• PC & PE are most abundant phospholipids in eukaryotic‫اــلمخلوقات‬

‫ حقيقهـ اــلنواـهـ‬cells.

• The primary route of synthesis uses choline and ethanolamine

obtained either from the diet or turnover ‫ اـعادهـ تـــصنيعـ‬of the body's
phospholipids.

• ‫مهمه‬In the liver, PC also can be synthesized from

phosphatidylserine (PS) and PE.
 1. Synthesis of PE and PC from preexisting choline
and ethanolamine

These synthetic pathways involve the phosphorylation of

choline or ethanolamine by ‫ اـنزيمـ‬kinases, followed by conversion
to the activated form, CDP-choline or CDP-ethanolamine‫ارجعـ اــلى‬
‫ اــلطريقهـ اــلثانيهـ لــتصنيعـ اــلفسفـولبدز لــكيتـــتوضح‬.

Finally, choline-phosphate or ethanolamine-phosphate is

transferred from the nucleotide (leaving CMP) to a molecule of
diacylglycerol (see Figure 17.5).

Significance of choline reutilization‫ل‬..‫ستعما‬.‫ ا‬.‫عاده‬.‫ا‬: The

reutilization of choline is important because, whereas humans can
synthesize choline de novo, the amount made is insufficient for our
needs. Thus, choline is an essential dietary nutrient with an adequate
intake of 550 mg for men and 420 mg for women.
 Role of PC in lung surfactant

1. The principal pathway for the synthesis of dipalmitoyl-

phosphatidylcholine 2 ‫ـلسيرفاكتينتـنظر رقمـ‬
‫ا‬ ‫(داـخلهـ فـــياــلتركيباــالساسيلـ‬DPPC, o
dipalmitoylecithin). In DPPC, positions 1 and 2 on the glycerol are
occupied by palmitate.
2. DPPC, made and secreted by granular pneumocytes, is the
major lipid component of lung surfactant--the extracellular fluid
layer lining the alveoli.
3. Surfactant serves to decrease the surface tension of this fluid layer,
reducing the pressure needed to reinflate alveoli, thereby preventing
alveolar collapse (atelectasis).
4. Respiratory distress syndrome (RDS) in pre-term infants is associated
with insufficient surfactant production, and is a significant cause of all
neonatal deaths in western countries.
5. Lung maturity of the fetus can be gauged by determining the ratio of
DPPC to sphingomyelin, usually written as the L (for lecithin)/S ratio,
in amniotic fluid.
6. A ratio of 2 or above ) ‫ اــلنسبهـ اــلسليمهـ ( مهمهـ‬is evidence‫دليل‬
of maturity, because it reflects the major shift from
sphingomyelin to DPPC synthesis that occurs in the
pneumocytes at about 32 weeks of gestation.
7. 1‫العالج )) مهمه‬- Lung maturation can be accelerated ‫تسرع‬
by giving the mother glucocorticoids shortly before
delivery. 2 ‫طريقه اخرى‬-Administration of natural or
synthetic surfactant (by intratracheal instillation ‫تقطير عبر‬
‫ )القصبه الهوائيه‬is also used in the prevention and treatment
of infant RDS.
8. Respiratory distress syndrome due to an insufficient
amount of surfactant can also occur in adults whose
surfactant producing pneumocytes have been damaged or
destroyed, for example, as an adverse side effect of
immuno-suppressive medication or chemotherapeutic
drug use.
2: Synthesis of PC from phosphatidylserine (PS) in
liver .‫لمكانمهم‬..‫ا‬:

1. The liver requires a mechanism for producing PC, even when free
choline levels are low, because it exports ‫ تـــصدر‬significant
amounts of PC in the bile and as a component of serum lipoproteins.
2. To provide the needed PC, PS is decarboxylated‫ تـــحولاــلى‬to
phosphatidylethanolamine (PE) by ‫ بـــواـسطهـ اـنزيمـ‬PS
decarboxylase, an enzyme requiring pyridoxal phosphate as a
cofactor.
3. PE then undergoes 3 methylation steps to produce PC, as
illustrated in Figure 17.6.
4. S-adenosylmethionine (SAM) is the methyl group donor lead to
S-adenosylhomocysteine
 C. Phosphatidylserine (PS)

The primary pathway for synthesis of PS in mammalian

tissues is provided by the base exchange reaction, in which
the ethanolamine of PE is exchanged for free serine (see
Figure 17.6).

This reaction, although reversible, is used primarily to

produce the PS required for membrane synthesis.
Phospholipid Lectuer#2
 D. Phosphatidylinositol (PI)

PI is synthesized from free inositol and CDP-diacylglycerol as

shown in Figure 17.5. ‫اــلطريقاــالولىلــصناعهـ اــلفسفـولبدز ويمكنصــناعتهـ‬
‫بـــاــلطريقهـ اــلثانيهـ كـما فـــياــلشريحهـ اــلقادمهـ‬

‫ مهمه‬: PI is an unusual phospholipid in that it often contains stearic

acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol.

‫مهمه جدا‬PI, therefore, serves as a reservoir ‫ خازن‬of arachidonic acid

( ‫ االركانيود اسد هو ماده اوليه تتحول الى عوامل االلتهاب‬: ‫ ) معلومه‬in membranes
and, thus, provides the substrate for prostaglandin ‫عامل التهاب‬
synthesis when required.
1. Role of PI in signal transmission .‫الشاره‬..‫قل ا‬..‫ ن‬across membranes:

a. The phosphorylation of membrane-bound phosphatidylinositol

produces polyphosphoinositides, for example,
phosphatidylinositol 4,5- bisphosphate (PIP2).

b. The degradation of PIP2 by phospholipase C occurs in response

to the binding of neurotransmitters, hormones, and growth factors
to receptors on the cell membrane (Figure 17.8).

c. The products of this degradation, inositol 1,4,5-trisphosphate

(IP3) and diacylglycerol (DAG), mediate the mobilization of
intracellular calcium and the activation of PKC, which act
synergistically to evoke‫ يــستدعي‬specific cellular responses. Signal
transmission across the membrane is completed.
‫نقل االشاره عبر الغشاء الخلوي‬
‫يــحدثفـــسفرهـ لــل‪PI1-‬‬
‫فينتج المركب اللي بالصوره‬
‫عند وجود اـشارهـ مناــلخارج ‪2-‬‬
‫كـهـرموناو غيرهـ يــنكسر‬
‫اــلمركباــلليبـــاــلصورهـ ويعطي‬
‫اــلكحول( اـينوزيتول) معـ‬
‫اــلفسفـور و يــعطي‬
‫‪Diglycrol‬‬
‫هذهـ اــلعمليهـ تـــحفـز اــالشاراـت‪3-‬‬
‫اــلخلويهـ‬

‫الصورة بالشريحه القادمه‬

‫تسهل كل الموضوع‬
‫مهمه وتسهل الموضوع‬
‫وخصوصا االسهم‬
 2. Role of PI in membrane protein anchoring .‫دعيم‬..‫ت‬

a. Specific proteins can be covalently ‫ بـــراـبطهـ تـــساهميهـ‬attached via a

carbohydrate bridge to membrane bound PI (Figure 17.9).

b. Examples of such proteins include alkaline phosphatase (a digestive

enzyme found on the surface of the small intestine that attacks
organic phosphates), and acetylcholine esterase (an enzyme of the
postsynaptic membrane that degrades the neurotransmitter
acetylcholine).

c. Cell surface proteins bound to glycosyl phosphatidylinositol (GPI)

are also found in a variety of parasitic protozoans‫( اــلطفيليات‬for
example, Trypanosomes and Leishmania).
d. Being attached to a membrane lipid rather than being an
integral part of the membrane) allows GPI-anchored proteins
rapid lateral mobility on the surface of the plasma membrane.

e. The protein can be cleaved from its anchor by the action of

phospholipase C ‫ مهمهـ‬releasing diacylglycerol.

f. A deficiency in the synthesis of GPI in hematopoietic ‫تـــكوين‬

‫ اــلدمـ‬cells results in a hemolytic disease, paroxysmal nocturnal
hemoglobinuria.
 E. Phosphatidylglycerol (PG) and cardiolipin

 PG occurs in relatively large amounts in mitochondrial

membranes and is a precursor of cardiolipin.

 It is synthesized by a two-step reaction from CDPdiacylglycerol

and glycerol 3-phosphate.

 Cardiolipin (diphosphatidylglycerol, is composed of two

molecules of phosphatidic acid connected by a molecule of glycerol.

 It is synthesized by the transfer of diacylglycerophosphate from

CDP-diacylglycerol to a preexisting molecule of
phosphatidylglycerol.
 F. Sphingomyelin

 Sphingomyelin, a sphingosine-based
phospholipid, is a ‫ مهمهـ‬major structural lipid in
the membranes of nerve tissue.
 The synthesis of sphingomyelin is shown
in Figure, Briefly, palmitoyl CoA
condenses with serine, as coenzyme A and
the carboxyl group (as CO2) of serine are
lost.
 This reaction, like the decarboxylation
reactions involving amino acids, requires
pyridoxal phosphate (a derivative of
vitamin B6) as a coenzyme.
 The product is reduced in an NADPH-requiring reaction to
sphinganine, which is acylated at the amino group with one of a
variety of long-chain fatty acids, and then desaturated to produce
‫مهمهـ‬a ceramide--the immediate precursor of sphingomyelin.

 ‫مهمه‬A ceramide with a fatty acid thirty carbons long is a major

component of skin, and regulates skin's water permeability.

 Phosphorylcholine from phosphatidylcholine is transferred to the

ceramide, producing sphingomyelin and diacylglycerol.

 Sphingomyelin of the myelin sheath contains predominantly ‫داـئما‬

longer-chain fatty acids such as lignoceric acid and nervonic
acid.
whereas gray matter of the brain has sphingomyelin that contains
primarily stearic acid.
 IV. DEGRADATION OF PHOSPHOLIPIDS

 The degradation of phosphoglycerides is performed by

phospholipases ‫ مهمهـ جـدا جـدا جـدا‬found in all tissues and pancreatic
juice.

 A number of toxins and venoms ‫ ســمومـ‬have phospholipase

activity, and several pathogenic bacteria (Baccili) produce
phospholipases that dissolve cell membranes and allow the
spread of infection.

 ) ‫ مهمه ( حاله خاصه‬Sphingomyelin is degraded by the lysosomal

phospholipase, sphingomyelinase.
 A. Degradation of phosphoglycerides

a. Phospholipases hydrolyze ‫ يــكسر‬the phosphodiester bonds of

phospho- glycerides, with each enzyme cleaving phospholipid
at a specific site.
b. The major enzymes responsible for degrading phosphoglycerides
are shown in Figure.

c. Removal of the fatty acid from carbon 1 or 2 of a

phosphoglyceride produces a lysophosphoglyceride, which is the
substrate for lysophospholipases.

d. Phospholipases release molecules that can serve as messengers

(DAG and IP3), or that are the substrates for synthesis of
messengers (arachidonic acid).
e. ‫ مهمه‬Phospholipases are responsible not only for degrading
phospholipids, but also for "remodeling ‫ "تغيير اشكالهم‬them.

f. For example, phospholipases A1 and A2 remove specific fatty acids

from membrane-bound phospholipids; these can be replaced with
alternative fatty acids using fatty acyl CoA transferase.

g. This mechanism is used as one way to create the unique

lung surfactant, dipalmitoylphosphatidylcholine (see p. 202), and to
insure that carbon 2 of PI (and sometimes of PC) is bound to
arachidonic acid.
 B. Degradation of sphingomyelin

a. 1 ‫يتم الفصل على مرحلتين‬-Sphingomyelin is degraded by

sphingomyelinase, a lysosomal enzyme that hydrolytically removes
phosphorylcholine, leaving a ceramide 2 .‫مهمه‬-The ceramide is, in
turn, cleaved by ceramidase into sphingosine and a free fatty acid
(Figure 17.12).

b. The ceramide and sphingosine released by the degradation of

sphingomyelin play a role as intracellular messengers.

c. ‫ مهممهـ‬Ceramides appear to be involved In the response to stress, and

sphingosine inhibits protein kinase C.

d. ‫مهمهـ‬Niemann-Pick disease (Types A and B) is an autosomal recessive

disease caused by the inability to degrade sphingomyelin. The
deficient enzyme is sphingomyelinase-A type of phospholipase C.
e. In the severe infantile form (type A), the liver and spleen
are the primary sites of lipid deposits and are, therefore, tremendously
enlarged. The lipid consists primarily of the
sphingomyelin that cannot be degraded (Figure 17.13).

f. Infants with this disease have rapid, progressive

neurodegeneration deposition of sphingomyelin in CNS,
and they die in early childhood.

g. A less severe variant (type B) causes little to no damage to neural

tissue, but lungs, spleen, liver, and bone marrow are affected,
resulting in a chronic form of the disease, with a life expectancy
only to early adulthood.
h. Although Niemann-Pick disease occurs in all ethnic groups.
both type A and B occur with greater frequency in the
Ashkenazi Jewish )‫ يــهـود اـشناكاز ( اـحسسسسسسسسسسسسن‬population than
in the general population.

i. In the Ashkenazi Jewish population, the incidence of type A

is 1:40,000 live births, and that of type B is 1:80,000.

j. The incidence of Niemann-Pick disease in the general

population is less than 1:100,000.
 Conclusions
1. Structure of Glycerophospholipids and sphingolipids.

3. Synthesis of phospholipids: Phosphatidic acid, PC, PE 

and PC, cardiolipin and sphingomyelin etc.

4. Degradation of phospholipids by phosphalipases.

5. Role of phosphatidyl choline in lung surfactant

6. Role of PI in signal transduction and membrane

anchoring .
‫‪THANK YOU‬‬

‫هللا يقلع بليس اللي حطك دكتور‬