Msb 203...cardio res sys.tg.pl.sl

MSB 203: CARDIORESPIRATORY SYSTEM

Dr. G.K. Maiyoh
Department of Medical Biochemistry

GKM/MUSOM.MEDBIOC.MSB203.CARDIORESSYS.2013
March 20, 2013 1

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 .

GKM/MUSOM.MEDBIOC.MSB203.CARDIORESS
March 20, 2013 YS.2013 2

Lecture Outline
1. Introduction to Lipid

2. Overview of phospholipids.

3. Structure of Glycerophospholipids and sphingolipids.

4. Synthesis of phospholipids: Phosphatidic acid, phosphatidyl-choline,
ethanolamine and serine, cardiolipin and sphingomyelin etc.

5. Degradation of phospholipids by phosphalipases.

6. Role of phosphatidyl choline in lung surfactant

7. Role of phsophatidylinositol in signal transduction and
membrane anchoring .

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Lipids defined

•A diverse group of compounds found in all living
cells, insoluble in water but soluble in organic solvents
such as ether, acetone and chloroform

Lipids classification

- Fatty acids (saturated/unsaturated)
- Glycerol
-Triglycerides
-Phospholipids (glycero/sphingo)
-Sterols (cholesterol and cholesterol esters)

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Cholesterol

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Fatty Acids
The Length of the Carbon Chain
long-chain, medium-chain, short-chain
The Degree of Unsaturation
saturated, unsaturated, monounsaturated,
polyunsaturated
The Location of Double Bonds
omega-3 fatty acid, omega-6 fatty acid

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The Length of the Carbon Chain

Short-chain Fatty Acid
(less than 6 carbons)

Medium-chain Fatty Acid
(6-10 carbons)

Long-chain Fatty Acid
(12 or more carbons)
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Phosphatidic acid Biosynthesis
TG and phospholipids share the same initial
synthesis pathway
TG and phospholipids both contain fatty acids linked
by ester bonds to a glycerol , and are described as
glycerolipids .
The synthesis pathway starts by reducing
dihydroxyacetone phosphateto glycerol
phosphate, with NADH as the reductant.
NAD+ dependent glycerol phosphate dehydrogenase
dihydroxyacetone phosphate + NADH + H+ L-glycerol-3-
phosphate + NAD+

(Alternatively, existing glycerol molecules may be
phosphorylated by glycerol kinase.

glycerol kinase
glycerol + ATP L-glycerol-3-
phosphate + ADP

Formation of active CoA thioester
This is followed by two successive additions of acyl
esters.
Fatty acid (typically 16-18 C atoms) is first
converted to the active CoA thioester by acyl CoA
synthetase:
acyl CoA synthetase
 stearate (18:0) + HSCoA + ATP stearoyl-CoA +
5'-AMP + PPi

Acylglycerols
Acyl-CoA is then used to donate acyl ester groups to the
glycerol backbone:
acyltransferase
L-glycerol-3-phosphate + acyl-CoA 1-acylglycerol-3-
phosphate + HSCoA

acyltransferase
1-acylglycerol-3-phosphate + stearoyl-CoA 1,2-diacylglycerol-3-phosphate + HSCoA

Phosphatidic acid

1. glycerol phosphate dehydrogenase
2. glycerol kinase
3. acyl transferase

Phosphatidic acid
The last product, 1,2-diacylglycerol-3-phosphate, is
also known as phosphatidic acid
Its phospholipid derivatives are phosphatidyl-X.

Phospholipids also tend to have a saturated fatty
acid in position 1 and an unsaturated fatty acid in
position 2.
The fat synthesis (TG) pathway branches here
from glycerophospholipid synthesis

TG formation
Phosphate is first removed by phosphatidic acid
phosphatase,
The acyltransferase can then add the third acyl
ester group tomake triacylglycerol (or fat)

Phospholipid
 Polar compounds composed of alcohol attached by a
phosphodiester bridge to either diacylglycerol or sphingosine.

 Amphipathic in nature, has a hydrophilic head (phosphate +
alcohol e.g., 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 on next slide

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Glycero-
phospholipids

Phosphatidic acid

4 major
glycerophospholipids
are polar/charged:

 Membrane phospholipids also function as :
 a reservoir for intracellular messengers, and,
 for some proteins, phospholipids serve as anchors
to cell membranes.

 Non-membrane-bound phospholipids serve additional
functions in the body, for example,
•1 as components of lung surfactant and
•2 essential components of bile, where their
detergent properties aid "in the solubilization of
cholesterol.

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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)

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(Cardiolipin)
Two molecules of phosphatidic acid esterified through phosphate
to an additional molecule of glycerol are called cardiolipin. (see
next slide)

This is the only human glycerophospholipid that is antigenic.

cardiolipin is recognized by antibodies raised against Treponema
the bacterium that causes syphylis

[Cardiolipin is an important component of the inner
mitochondrial membrane and bacterial membranes.]

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• Diphosphatidyl glycerol (cardiolipin)

O O
RCO-CH2 CH2-OCR
O O
RCO-CH CH-OCR
O OH O
CH2-O-P-O-CH2-CH-CH2-O-P-O-CH2
O- O-
glycerol

Plasmalogens

When the fatty acid at carbon 1 of a glycerolphospholipid is
replaced by an unsaturated alkyl group attached by an
ether (rather than by an ester) linkage to the core glycerol :
molecule, a plasmalogen is produced.

Phosphatidalethanolamine is abundant in nerve tissue is a
plasmalogen.

Phosphatidalcholine (abundant in heart muscle) is the other
quantitatively significant ether lipid in mammals.

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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 linkage, producing a ceramide,
which serve as a precursor of glycolipids.

The alcohol group at carbon 1 of sphingosine is esterified to
phosphorylcholine, producing sphingomyelin, the only
significant sphingophospholipid in humans.

Sphingomyelin is an important component of the myelin of nerve
fibers (myelin sheath) that insulates and protects neuronal fibers
of the central nervous system.
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Synthesis of Phospholipid

1. Glycerophospholipid (GP) synthesis involves either
a. The donation of phosphatidic acid from CDP-diacylglycerol to
an alcohol, or
b. The donation of 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 to be added by linkage with CDP.
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1

CMP

2

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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 synthesized in the Smooth ER-- then transported to
Golgi apparatus and then membranes organelles or plasma
membrane, or are secreted by exocytosis

6. There are two classes of phospholipids: Those have either glycerol as
a backbone or contain sphingosine.

7. Both classes are found in membranes and play a role in the
generation of lipid-signaling molecules.

March 20, 2013 YS.2013 29

Synthesis of phosphatidylethanolamine (PE) &
phosphatidylcholine (PC)

• PC & PE are most abundant phospholipids in eukaryotic cells.

• The primary route of synthesis uses choline and ethanolamine
obtained either from the diet or turnover of the body's phospholipids.

• In the liver, PC also can be synthesized from phosphatidylserine
(PS) and PE.

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1. Synthesis of PE and PC from preexisting choline
and ethanolamine

These synthetic pathways involve the phosphorylation of
choline or ethanolamine by kinases, followed by conversion to
the activated form, CDP-choline or CDP-ethanolamine

Finally, choline-phosphate or ethanolamine-phosphate is
transferred from the nucleotide (leaving CMP) to a molecule of
diacylglycerol.

Significance of choline reutilization 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.
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Role of PC in lung surfactant

1. The major lipid component of lung surfactant--the extracellular fluid
layer lining the alveoli is dipalmitoyl-phosphatidylcholine (DPPC, or
dipalmitoylecithin).
In DPPC, positions 1 and 2 on the glycerol are occupied by palmitate.
2. DPPC, made and secreted by granular pneumocytes
3. Surfactant serves to decrease the surface tension of this fluid layer,
reducing the pressure needed to reinflate alveoli, thereby preventing
alveolar collapse (atelectasis).
3. Respiratory distress syndrome (RDS) in pre-term infants is associated
with insufficient surfactant production, and is a significant cause of
neonatal deaths .
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.
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6. A ratio of 2 or above is evidence 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. 1- Lung maturation can be accelerated by giving the
mother glucocorticoids shortly before delivery. 2-
Administration of natural or synthetic surfactant (by
intratracheal instillation is 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.
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2: Synthesis of PC from phosphatidylserine (PS) in
liver

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

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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

This reaction, although reversible, is used primarily
to produce the PS required for membrane synthesis.

March 20, 2013 YS.2013 36

D. Phosphatidylinositol (PI)

PI is synthesized from free inositol and CDP-diacylglycerol
PI is an unusual phospholipid in that it often contains
stearic acid on carbon 1 and arachidonic acid on carbon 2
of the glycerol.

PI, therefore, serves as a reservoir of arachidonic acid in
membranes and, thus, provides the substrate for
prostaglandin synthesis when required.

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March 20, 2013 YS.2013 38

1. Role of PI in signal transmission across membranes:

a. The phosphorylation of membrane-bound phosphatidylinositol
produces polyphosphoinositides, for example,
phosphatidylinositol 4,5- bisphosphate (PIP2). (See next slide)

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.

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 specific cellular responses.
Signal transmission across the membrane is completed.
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2. Role of PI in membrane protein anchoring

a. Specific proteins can be covalently attached via a carbohydrate
bridge to membrane bound PI.

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 (for example,
Trypanosomes and Leishmania).

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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 releasing diacylglycerol.

f. A deficiency in the synthesis of GPI in hematopoietic cells
results in a hemolytic disease, paroxysmal nocturnal
hemoglobinuria.

March 20, 2013 YS.2013 44

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.

March 20, 2013 YS.2013 45

Sphingomyelin

 Sphingomyelin, a sphingosine-based
phospholipid, is a major 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.
March 20, 2013 YS.2013 46

 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
a ceramide--the immediate precursor of sphingomyelin.

 A 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
longer-chain fatty acids such as lignoceric acid and nervonic
acid.
whereas gray matter of the brain has sphingomyelin that contains
primarily stearic acid.
March 20, 2013
YS.2013 47

IV. DEGRADATION OF PHOSPHOLIPIDS

 The degradation of phosphoglycerides is performed by
phospholipases found in all tissues and pancreatic juice.

 A number of toxins and venoms have phospholipase activity, and
several pathogenic bacteria (Baccili) produce phospholipases that
dissolve cell membranes and allow the spread of infection.

 Sphingomyelin is degraded by the lysosomal phospholipase,
sphingomyelinase.

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A. Degradation of phosphoglycerides

a. Phospholipases hydrolyze the 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 on next slide.

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).
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e. Phospholipases are responsible not only for degrading phospholipids,
but also for remodeling them.

e. 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 and to
insure that carbon 2 of PI (and sometimes of PC) is bound to
arachidonic acid.

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B. Degradation of sphingomyelin
a. 1-Sphingomyelin is degraded by sphingomyelinase, a lysosomal
enzyme that hydrolytically removes phosphorylcholine, leaving a
ceramide.
2-The ceramide is, in turn, cleaved by ceramidase into sphingosine
and a free fatty acid.

b. The ceramide and sphingosine released by the degradation of
sphingomyelin play a role as intracellular messengers.

c. Ceramides appear to be involved In the response to stress, and
sphingosine inhibits protein kinase C.

d. Niemann-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.
March 20, 2013 YS.2013 52

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 (slide 42).

f. Infants with this disease have rapid, progressive
neurodegenerative 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.

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h. Although Niemann-Pick disease occurs in all ethnic groups.
both type A and B occur with greater frequency in the
Ashkenazi Jewish ) population 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.

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Conclusions
1.Introduction to lipids
2.Structure of Glycerophospholipids and sphingolipids.
3.Synthesis TG,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 .

March 20, 2013 YS.2013 56

THANK YOU

March 20, 2013 YS.2013 57

Msb 203...cardio res sys.tg.pl.sl

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