December 6, 2011
Lecturer: Eileen M. Lafer
MEMBRANE LIPIDS I and II:
GLYCEROPHOSPHOLIPIDS AND SPHINGOLIPIDS
Reading:
Stryer Edition 6: Chapter 26
OBJECTIVES:
1.
Know the general structures of the principle classes of storage and
membrane lipids.
2.
Recognize the structures of the major glycerophospholipids
(phosphatidic acid, phosphatidyl serine, phosphatidyl choline, phosphatidyl
ethanolamine, phosphatidyl inositol, cardiolipin).
3.
Understand the chemical differences between -ester linked and -ether
linked phospholipids.
4.
Recognize the structures of the major sphingolipids: ceramide,
sphingomyelin, glucosylcerebroside, lactosylceramide, ganglioside GM2.
5.
Understand the role that sphingolipids play as blood group
determinants.
6.
Know the pathways for the degradation of phospholipids and
sphingolipids.
7.
Know the genetic defects that lead to the following diseases:
Generalized gangliosidosis, Tay-Sachs disease, Fabry's disease, Sandhoff's
disease, Gaucher's disease, and Niemann-Pick disease.
8.
Understand how lipids can act as signaling molecules in cells.
9.
Know the mechanism of action of the non-steroidal anti-inflammatory
drugs.
10.
Know how phosphatidate is synthesized.
11.
Understand both pathways of glycerophospholipid synthesis:
a. Via CDP-diacylglycerol intermediate (PI, PG, CL)
b. Via CDP-head group intermediate (PC, PE)
12.
Understand the pathways that involve the modification of
phosphatidylethanolamine.
13.
Understand the cause of respiratory distress syndrome.
14.
Know how sphingomyelin is synthesized.
THE PRINCIPLE CLASSES OF
STORAGE AND MEMBRANE LIPIDS
All these lipids have either glycerol or sphingosine as the
backbone. A third class of membrane lipids, the sterols, are
discussed separately.
L-GLYCEROL 3-PHOSPHATE:
The backbone of phospholipids
This compound can also be called D-glycerol 1-phosphate.
Glycerol is pro-chiral, it has no asymetric carbons, but attachment of phosphate to either end makes it
chiral.
GLYCEROPHOSPHOLIPIDS
1. The common glycerophospholipids are diacylglycerols linked
to head-group alcohols through a phosphodiester bond.
GLYCEROPHOSPHOLIPIDS
Phosphatidic acid, a phosphomonoester, is the parent compound
(X=H).
GLYCEROPHOSPHOLIPIDS
Each derivative is named for the head-group alcohol (X) with the
pre-fix "phosphatidyl-".
Each
derivative
is named
for the
headgroup
alcohol
(X) with
the pre-fix
"phosphati
dyl-".
In caridiolipin, two phosphatidic acids share a single glycerol,
hence it is also called diphosphatidly-glycerol.
GLYCEROPHOSPHOLIPIDS
2. The fatty acids can vary greatly between organisms, tissues
and cells.
In general, they contain a saturated C16 or C18 fatty acid at
C1 and a C18 to C20 unsaturated fatty acid at C2.
GLYCEROPHOSPHOLIPIDS
3. Common components of cell membranes.
STRUCTURES OF SOME COMMON
GLYCEROPHOSPHOLIPIDS
(lecithin)
SOME PHOSPHOLIPIDS HAVE
ETHER LINKED FATTY ACIDS
1. Plasmalogens have an ether-linked alkenyl chain where
most glycerophospholipids have an ester-linked fatty acid. The
head group alcohol is choline. ~50% of the heart phospholipids
are plasmalogens.
ETHER
ESTER
2. Platelet-activating factor has a long ether-linked alkyl chain
at C1. Acetic acid is ester-linked at C2, which makes it more
water soluble than most glycerophospholipids. The head-group
alcohol is choline.
Platelet-activating factor is a potent molecular signal released
from leucocytes that stimulates platelet aggregation and serotonin
release. It also has a variety of effects on many tissues including
roles in inflammation and the allergic response.
THE PRINCIPLE CLASSES OF
STORAGE AND MEMBRANE LIPIDS
All these lipids have either glycerol or sphingosine as the
backbone. A third class of membrane lipids, the sterols, are
discussed separately.
SPHINGOLIPIDS
The 3-carbon
backbone is
analogous to the
3-carbons of
glycerol.
At C3 there is the
long chain amino
alcohol
sphingosine.
SPHINGOLIPIDS
At C2 there is a
fatty acid which is
usually saturated or
monounsaturated,
and can be either
16,18, 22, or 24
carbons long.
SPHINGOLIPIDS
Ceramide is the
parent compound.
Other polar head
groups can be
attached at position
X.
SPHINGOLIPIDS
Glycosphingolipids
are a sub-group of
sphingolipids that
contain sachharide
headgroups
SIMILARITIES BETWEEN
PHOSPHATIDYL CHOLINE
(A GLYCEROPHOSPHOLID) AND
SPHINGOMYELIN (A SPHINGOLIPID)
choline
choline
Prominent in myelin
sheath that surrounds
and insulates neurons
SPHINGOLIPIDS AT CELL
SURFACES ARE SITES OF
BIOLOGICAL RECOGNITION
1.
In humans at least 60 different sphingolipids have been
identified.
2.
Very prominent in neuronal plasma membranes.
3.
Carbohydrate moieties of sphingolipids define the human
blood groups.
4.
The kinds and amounts of gangliosides vary dramatically
during development.
GLYCOSPHINGOLIPIDS AS
DETERMINANTS OF BLOOD GROUPS
The human blood groups
(O, A, B) are determined
in part by the
oligosaccharide head
groups of these
glycosphingolipids.
Glc:D-glucose
Gal:D-galactose
GalNAc:N-acetyl-Dgalactosamine
Fuc:fucose
PHOSPHOLIPIDS AND
SPHINGOLIPIDS ARE DEGRADED IN
LYSOSOMES
1.
For each hydrolyzable bond in a glycerophospholipid there
is a specific hydrolytic enzyme in the lysosome.
2.
Phospholipase A1 hydrolyzes the fatty acid at C1.
3.
Phospholipase A2 hydrolyzes the fatty acid at C2.
4.
When one fatty acid is removed from either C1 or C2, a
lysophospholipase removes the remaining fatty acid.
5.
Phospholipases C and D each split one specific
phosphodiester bond in the head group.
A
A GLOBOSIDE
LACTOSYLCERAMIDE
GLUCOSYLCEREBROSIDE
GANGLIOSIDES
ARE
DEGRADED
BY A
SET OF
LYSOSOMAL
ENZYMES
A
A GLOBOSIDE
LACTOSYLCERAMIDE
GLUCOSYLCEREBROSIDE
These enzymes
catalyze the
stepwise removal
of sugar units,
finally yielding a
ceramide.
A
A GLOBOSIDE
LACTOSYLCERAMIDE
GLUCOSYLCEREBROSIDE
A genetic defect
in any one of
these hydrolytic
enzymes leads to
the accumulation
of gangliosides
in the cell, with
severe medical
consequences.
A
A GLOBOSIDE
LACTOSYLCERAMIDE
GLUCOSYLCEREBROSIDE
Genetic
counseling
can predict
and avert
many of
these
diseases.
NIEMANN-PICK DISEASE
Defect in Sphingomyelinase
Sphingomyelin accumulates in the brain, spleen,
and liver
Evident in infants.
Causes mental retardation and early death.
NIEMANN-PICK
DISEASE
TAY-SACHS DISEASE
Defect in Hexoaminadase
TAY-SACHS DISEASE
Ganglioside GM2 accumulates in the brain and spleen
TAY-SACHS DISEASE
Electron Micrograph from a portion of a brain of an infant
with Tay-Sachs disease showing abnormal ganglioside
deposits in the lysosomes:
TAY-SACHS DISEASE
Progressive retardation in development, paralysis,
blindness, and death by the age of 3 or 4 years.
TAY-SACHS
DISEASE
SUMMARY OF DEFECTS IN
GANGLIOSIDE CATABOLISM THAT
CONTRIBUTE TO HUMAN DISEASE
Medical Condition
Defective Enzyme
Major
Accumulating
Metabolite
Generalized Gangliosidosis
Beta-Galactosidase
GM1
Tay-Sachs Disease
Hexosaminidase A
GM2
Gaucher’s Disease
Glucocerebrosidase
Glucosylcerebroside
Niemann-Pick Disease
Sphingomyelinase
Sphingomyelin
Sandhoff’s Disease
Hexosaminidase A&B
A Globoside*
Fabry’s Disease
Alpha-Galactosidase A A Globoside*
*The globosides that are substrates for the defective enzymes in these diseases do not
have specific names, but are referred to by the broad term globoside.
LIPIDS AS SIGNALS :
1. Phosphatidyl Inositols and its
phosphorylated derivatives act to regulate cell
structure and metabolism.
2. Eicosanoids are paracrine hormones
derived from arachidonic acid-containing
membrane phospholipids. They are involved in
reproductive function, inflammation, fever, pain,
blood clot formation, blood pressure regulation,
gastric acid secretion, and other biological
processes.
PHOSPHATIDYLINOSITOLS
PIP2 is hydrolyzed by phospholipase C in response to hormonal signals. Both
of the metabolites produced act as intracellular messengers.
ARACHIDONIC ACID AND SOME
EICOSANOID DERIVATIVES
In response to hormonal signals, phospholipase A2
cleaves arachadonic-containing membrane lipids to
release arachidonic acid.
Arachidonic acid can then serve as a precursor for
several eicosanoids including prostaglandin E1,
thromboxane A1 and leukotriene A4:
Non-steroidal anti-inflammatory drugs (NSAIDS)
such as aspirin, naproxen, and ibuprofen block the
formation of prostaglandins and thromboxanes
from arachidonate by inhibiting the enzyme
cyclooxygenase (prostaglandin H2 synthase).
BIOSYNTHESIS OF MEMBRANE
PHOSPHOLIPIDS
1.
Synthesis of the backbone molecule (glycerol or
sphingosine).
2.
Attachment of fatty acids to the backbone in
ester or amide linkage.
3.
Addition of a hydrophilic head group joined to
the backbone through a phosphodiester linkage.
4.
In some cases, alteration or exchange of the
head group to yield the final phospholipid product.
TRIACYLGLYCEROLS AND
GLYCEROPHOSPHOLIPIDS ARE
SYNTHESIZED FROM THE SAME
PRECURSORS
(1) Formation of Glycerol-3-phosphate:
acyl groups
(2) Fatty
are activated by
formation of fatty
acyl-CoA.
Then they are
transferred to ester
linkage with
glycerol-3phosphate.
PHOSPHATIDIC ACID
= DIACYLGLYCEROL
3-PHOSPHATE
THERE ARE TWO STRATEGIES FOR
ATTACHING HEAD GROUPS
Diacylglcerol
activated with CDP:
Phosphatidylinositol
Cardiolipin
Phosphatidylglycerol
Headgroup
activated with CDP:
Phosphatidylcholine
Phosphatidylethanolamine
PHOSPHATIDIC
ACID IS THE
PRECURSOR
OF BOTH TRIACYLGLYCEROL
AND GLYCEROPHOSPHOLIPIDS
MODIFICATION
PATHWAYS:
Phosphatidylserine and
phosphatidylethanolamine
can be interconverted by a
reversible head group
exchange reaction.
MODIFICATION
PATHWAYS:
In mammals,
phosphatidylserine is
synthesized from
phosphatidylethanolamine
by this mechanism.
MODIFICATION
PATHWAYS:
This reaction is catalyzed by
phosphatidylethanolamineserine transferase.
Phosphatidylethanolamine
may also be converted to
phosphatidylcholine (lecithin)
by the addition of three
methyl groups to its amino
group.
S-adenothylmethione is the
methyl donor.
This reaction is catalyzed by
a methyltransferase.
The multiple pathways of
phospholipid biosynthesis
reflect the importance of
phospholipids in membrane
structure and function.
RESPIRATORY DISTRESS
SYNDROME:
Failure to synthesize enough dipalmitoyl
phosphatidylcholine which is an important component
of lung surfactant. It functions to reduce the surface
tension of the fluid that surrounds the alveoli of the
lung to prevent lung collapse at the end of the
expiration phase of breathing.
Premature infants may suffer from respiratory
distress syndrome because their immature lungs
do not synthesize enough dipalmitoyl phosphatidyl
choline.
SPHINGOLIPID BIOSYNTHESIS I
1. Synthesis of 18 carbon
sphinganine from palmitoylCoA and serine.
SPHINGOLIPID BIOSYNTHESIS I
2. Attachment of a fatty acid
in amide linkage to yield
N-acylsphinganine.
SPHINGOLIPID BIOSYNTHESIS II
3. Desaturation of the
sphinganine moiety to
form N-acylsphingosine.
SPHINGOLIPID BIOSYNTHESIS II
4. Attachment of a head
group to produce a
sphingolipid such as a
cerebroside or
sphingomyelin.