PHOSPHOLIPID METABOLISM & GLYCOLIPID METABOLISM

2.  PHOSPHOLIPIDS are polar, ionic compounds
composed of an alcohol that is attached by a
phosphodiester bridge to either diacyglycerol
or to sphingosine.
 PHOSPHOLIPIDS are amphipathic in nature
that is, each has a hydrophilic head.
 The hydrophobic portion of the molecules are
associated with other non polar constituents
of membranes, including glycolipids, protein,
and cholesterol.

3.  There are two classes of phospholipids: those that
have glycerol (from glucose) as a backbone and
those that have sphingosine (from serine and
palmitate).
A. Phosphoglycerides- Phospholipids that
contain glycerol are called phosphoglycerides
(or glycerophospholipids). Phosphoglycerides
constitute the major class of phospholipids and
are the predominant lipids in membranes. All
contain (or are derivatives of) phosphatidic
acid (PA), which is diacylglycerol (DAG) with a
phosphate group on carbon 3. PA is the simplest
phosphoglyceride and is the precursor of the
other members of this group.

4. Figure:18.1

5. 1. Phospholipids From
Phosphatidic Acid
And An Alcohol: The
phosphate group on
PA can be esterified
to another compound
containing an alcohol
group.

6. 2. Cardiolipin: Two molecules of PA esterified
through their phosphate groups to an additional
molecule of glycerol is called cardiolipin. Note
that cardiolipin is an important component of
the inner mitochondrial membrane and
bacterial membrane.
3. Plasmalogens: When the fatty acid at carbon 1
of a glycerophospholipid is replaced by an
unsaturated alkyl group attached by an ether
(rather than by an ester) linkage to the core
glycerol molecule, an ether phosphoglyceride
known as a plasmalogen is produced.

7. B. Sphingomyelin- The backbone of
sphingomyelin is the amino alcohol sphingosine,
rather than glycerol. [Note: The fatty acids
found most frequently in sphingomyelin are
palmitic, stearic, lignoceric and nervonic acid.
The alcohol group at carbon 1 of sphingosine is
esterified to phosphorylcholine, producing
sphingomyelin, an important constituentof this
myelin of nerve fibers. [Note: The myelin sheath
is a layered, membranous structure that
insulates and protects neuronal fibers of the
central nervous system.]

8.  Phosphoglycerides synthesis involves either
the donation of (PA) phosphatic acid from
cytidine diphosphate (CDP)-diacylglycerol to
an alcohol or the donation of the
phosphomonoester of the alcohol from CDP-
alcohol to 1,2-diacylglycerol
 Most phospholipids are synthesized in the
smooth endoplasmic reticulum (ER). From
there, they are transported to the Golgi
apparatus and then to membranes of
organelles or the plasma membrane or are
secreted from the cell by exocytosis.

9. A. Phosphatidic acid: PA is the precursor of many
other phosphoglycerides. [Note: Essentially all
cells except mature erythrocytes can synthesize
phospholipids, whereas triacyl- glycerol synthesis
occurs essentially only in liver, adipose
tissue, lactating mammary glands, and intestinal
mucosal cells.]
B. Synthesis of phosphatidylethanolamine
(PE) and phosphatidylcholine (PC): PC and
PE are the most abundant phospholipids in most
eukaryotic cells. The primary route of their
synthesis uses choline and ethanolamine obtained
either from the diet or from the turnover of the
body’s phospholipids.

10. 1. Synthesis of PE and PC from preexisting
choline and ethanolamine
a. Significance of choline reutilization
b. Role of phosphatidylcholine in lung surfactant:
This phospholipid is a major lipid component of
lung surfactant, which is the extracellular fluid
layer lining the alveoli. Surfactant serves to
decrease the surface tension of this fluid layer,
thereby preventing alveolar collapse.
Respiratory distress syndrome (RDS) in preterm
infants is associated with insufficient surfactant
production and/or secretion and is a significant
cause of all neonatal deaths in Western
countries.

11. 2. De novo synthesis of phosphatidylcholine from
phosphatidylserine in the membrane
C. Phosphatidylserine- PS synthesis 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.
D. Phosphatidylinositol- PI is synthesized from free
inositol and CDP-diacylglycerol as shown. PI is an
unusual phospholipid in that it most frequently
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.

12. 1. Role of PI in signal transmission across
membranes: The phosphorylation of membrane
bound phosphatidylinositol occurs in response to
the binding of a variety of neurotransmitters,
hormones, and growth factors to receptors on
cell membrane.
2. Role of PI in membrane protein
anchoring:[Note: Examples such protiens
include alkaline phosphate, acetylcholine
esterase and lipoprotien lipase.] The protein
can be cleaved from its anchor by the action of
phospholipase C, releasing diacylglycerol, a
second messenger that can activate protein
kinase C.

13. E. Phosphatidylglycerol (PG):
Phosphatidylglycerol occurs in relatively
large amounts in mitochondrial membranes
and is a precursor of cardiolipin. It is
synthesized by a two-step reaction from CDP-
diacylglycerol and glycerol.
F. Cardiolipin: Cardilipin
(diphosphatidylglycerol) is composed of two
molecules of phosphatidic acid connected
by a molecule of glycerol.

14. G. Plasmalogens:
 Plasmalogens: There are major classes of
plasmalogens: phosphatidalcoholines,
phosphatidalethanolamines, and
phophatidalserines
 Myelin contains large amount of
ethanolamine plasmalogen, and heart
muscles contains large amounts of choline
plasmalogen. One plasmalogen 1-alkaneyl-2 –
acetyl-phosphatidalcholine is a very powerful
chemical mediator. It has potent physiologic
actions on a variety of cell types.

15. H. Sphingomyelin: Sphingomyelin is one of
the principal structural lipids of membranes
of nerve tissue. This class of phospholipid
has sphingosine rather that glycerol as the
alcohol portion of the molecule. [Note:
sphingomyelin of the myelin sheath contains
predominantly longer chain fatty acids such
as ligonceric and nervonic acids where as
gray matter of the brain has sphingomyelin
that contains primarily with stearic acid.]

16.  The degradation of phosphoglycerides is
performed by phospholipases found in all
tissues and pancreatic juice (for a discussion
of phospholipid digestion. A number of toxins
and venoms have phospholipase activity, and
several pathogenic bacteria produce
phospholipases that dissolve cell membranes
and allow the spread of infection.
Sphingomyelin is degraded by the lysosomal
phospholipase, sphingomyelinase.

17. A. Degradation of phosphoglycerides:
Phospholipases hydrolyze the
phosphodiester bonds of phosphoglycerides,
with each enzyme cleaving the phospholipid
at a specific site. Each enzyme cleaves the
phospholipid at a specific type.[Note:
Phospholipases are responsible not only for
degrading phospholipids, but also for
“remodelling” them.]

18. B. Degradation of sphingomyelin:
Sphingomyelin is degraded by sphingomyelinase, a
lysosomal enzyme that hydrolytically removes
phosphorylcholine, leaving a ceramide. The ceramide is, in
turn, cleaved by ceramidase into sphingosine and a free fatty
acid. Niemann-Pick disease (Types A and B) is an autosomal-
recessive disease caused by the inability to degrade
sphingomyelin due to a deficiency of sphingomyelinase, a type
of phospholipase C. In the severe infantile form (Type A, which
shows less than 1% of normal enzymic activity), the liver and
spleen are the primary sites of lipid deposits and are,
therefore, greatly enlarged. The lipid consists primarily of the
sphingomyelin that cannot be degraded (Figure 17.13). Infants
with this lysosomal storage disease experience rapid and
progressive neurodegeneration as a result of deposition of
sphingomyelin in the CNS, and they die in early childhood.

20.  Glycolipids are molecules that contain both
carbohydrate and lipid components. Like the
phospholipid sphingomyelin, glycolipids are
derivatives of ceramides in which a long-chain fatty
acid is attached to the amino alcohol sphingosine.
They are, therefore, more precisely called
glycosphingolipids. Like the phospholipids,
glycosphingolipids are essential components of all
membranes in the body, but they are found in
greatest amounts in nerve tissue. They are located
in the outer leaflet of the plasma membrane, where
they interact with the extracellular environment. As
such, they play a role in the regulation of cellular
interactions (for example, adhesion and
recognition), growth, and development.

21.  The glycosphingolipids differ from sphingomyelin in that
they do not contain phosphate, and the polar head function
is provided by a monosaccharide or oligosaccharide
attached directly to the ceramide by an O-glycosidic bond.
A. Neutral glycosphingolipids: The simplest neutral
(uncharged) glycosphingolipids are the cerebrosides.
These are ceramide monosaccharides that contain either
a molecule of galactose (forming ceramide-galactose or
galactocerebroside, the most common cerebroside found
in myelin or glucose. [Note: Members of a group of
galacto- or glucocerebrosides may also differ from each
other in the type of fatty acid attached to the
sphingosine.] As their name implies, cerebrosides are
found predominantly in the brain and peripheral nervous
tissue, with high concentrations in the myelin sheath.

22. B. Acidic glycosphingolipids: Acidic
glycosphingolipids are negatively charged at
physiologic pH. The negative charge is provided
by N-acetylneuraminic acid ([NANA], a sialic
acid in gangliosides, or by sulfate groups in
sulfatides.
1. Gangliosides: These are the most complex
glycosphingolipids and are found primarily in
the ganglion cells of the CNS, particularly at the
nerve endings.
2. Sulfatides: These sulfoglycosphingolipids are
sulfated galactocerebrosides that are negatively
charged at physiologic pH. Sulfatides are found
predominantly in the brain and kidneys.

23.  Synthesis of glycosphingolipids occurs
primarily in the Golgi by sequential addition
of glycosyl monomers transferred from UDP–
sugar donors to the acceptor molecule.
A. 1. Enzymes involved in synthesis: The
enzymes involved in the synthesis of
glycosphingolipids are glycosyl transferases,
each specific for a particular sugar
nucleotide and acceptor. [Note: These
enzymes may recognize both
glycosphingolipids and glycoproteins as
substrates.]

24. B. Addition of sulfate groups: A sulfate is
added to a galactocerebrocide by transfer
from the sulfate carrier, 3’-
phosphoadenosine-5’-phosphosulfate (PAPS),
to the 3’-hydroxyl group of the galactose, by
sulfotransferase. [Note: PAPS is also the
sulfur donor in the glcosaminoglycan
synthesis.

25.  Glycosphingolipids are internalized by endocytosis
as described for the glycosaminoglycans. All of
the enzymes required for the degradative process
are present in lysosomes, which fuse with the
endocytotic vesicles. The lysosomal enzymes
hydrolytically and irreversibly cleave specific
bonds in the glycosphingolipid. As seen with the
glycosaminoglycans and glycoproteins degradation
is a sequential process following the rule “last on,
first off,” in which the last group added during
synthesis is the first group removed in
degradation.

26.  In a normal individual, synthesis and
degradation of glycosphingolipids are
balanced, so that the amount of these
compounds present in membranes is
constant. If a specific lysosomal hydrolase
required for degradation is partially or totally
missing, a sphingolipid accumulates.
Lysosomal lipid storage diseases caused by
these deficiencies are called
sphingolipidoses.

27. A. Common properties of the sphingolipidoses:
A specific lysosomal hydrolytic enzyme is deficient in each
disorder. Therefore, usually only a single sphingolipid (the
substrate for the deficient enzyme)accumulates in the
involved organs in each disease.[NOTE : The rate of
biosynthesis of the accumulating lipid is normal] The enzyme
deficiencies cause death, usually soon after the first month
of life (with the exception of the adult form of Gaucher’s
diseases and of Fabry’s diseases.
B. Diagnosis of a sphingolipidosis:
A specific sphingolipidosis can be diagnosed from an analysis
of tissue samples, cultured fibroblast , penpheral leukocytes,
plasma , and / or amniotic fluid, for presence of enzyme
activity and for accumulated lipid.[NOTE: The sphingolipid
that that accumulates in the lysosomes in each disease is the
structure that cannot be further degraded due to the specific
enzyme defeciency.]

28. Figure:19.4