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chapter 19
Lipids li: Phospholipids, Glycosphingolipids, and Cholesterol
Synthesis of phosphatidylcholine can occur by base-
exchange
reaction,
by
methylation
of
phosphati-
dalethanolamine, or by the coupled action of phos-
pholipase
and
CDP-choline:cholinephosphotransferase
on phosphatidalethanolamine. Although the function of
most ether-containing phosphoglycerides is unknown, a
“platelet-activating factor” (PAF) that promotes platelet
aggregation has the following structure:
H 2C O R
O
II
H c —
C — O — C H
I
?
.
H
2
C — O — P — O — C H
2
C H
2
N (C H
3)3
I
c r
1 -A lk y l-2 -a c e ty l-sn -g ly c e ry l-3 -p h o s p h o c h o lin e
PAF released from IgE-sensitized basophilic leukocytes
(and probably other mononuclear cells, such as mast cells)
in response to antigen stimulation causes aggregation of
platelets and release of their granular constituents (e.g.,
serotonin). This action of PAF is potent and rivals that of
thromboxane A
2
(Chapter 18). PAF also is a potent anti-
hypertensive agent when given intravenously to hyperten-
sive rats. It is inactivated by deacetylation by a specific
acetylhydrolase.
Phosphosphingolipids
The
sphingomyelins
are structurally similar to phos-
phatidylcholine but contain N-acylsphingosine (ceramide)
instead of
5
n-l,
2
-diacylglycerol (Figure 19-6). They occur
in high concentration in myelin and in the brain and are a
nearly ubiquitous constituent of membranes.
Sphingolipid biosynthesis is catalyzed by membrane-
bound enzymes of the endoplasmic reticulum. Sphingo-
sine, an acylaminoalcohol, is synthesized from palmitoyl-
CoA and serine in a reaction that requires pyridoxal
phosphate, NADPH, and Mn2+ (Figure 19-7). The exact
pathway of ceramide synthesis is not known. The acyl
group may be added to the
2
-amino group of sphinganine,
hc-^
^
H
I
R — N — C H
O
H
2
C O P O C H p H
2
N (C H 3)s
cr
FIGURE 19-6
Structure of sphingomyelin.
either as a fatty acid (the reverse of hydrolysis of ceramide)
or from an acyl-CoA by an acyltransferase. In such a
pathway, the double bond in the aliphatic chain would
be inserted after the acylation step. Direct transfer of
an acyl group to sphingosine is an alternative pathway
of ceramide synthesis. The acyl groups of sphingolipids
may be those of long-chain fatty acids synthesized by the
fatty acid synthase complex (e.g., palmitic or stearic),
very-long-chain fatty acids synthesized by the micro-
somal chain elongation system (e.g., behenic, ligno-
ceric), monoenoic fatty acids (e.g., oleic, nervonic), or
a-hydroxy very-long-chain fatty acids. The presence of
transferases specific for different chain lengths deter-
mines the acyl composition of sphingolipids in a given
tissue.
Sphingomyelin is probably synthesized by an exchange
reaction in which the phosphorylcholine moiety of phos-
phatidylcholine is transferred to ceramide:
Ceramide + phosphatidylcholine —>
sphingomyelin + diacylglycerol
Synthesis of glycosphingolipids and sulfoglycosphin-
golipids involves the addition of sugar and sulfate
residues to ceramide from UDP-sugar derivatives or
the
activated
sulfate
donor
3'-phosphoadenosine-5'-
phosphosulfate (Chapter 17), and appropriate transferases.
These pathways are discussed in Chapter 16. Catabolism
of sphingolipids is by specific lysosomal hydrolases. Sev-
eral inherited disorders associated with the deficiencies of
these enzymes are discussed below.
19.2 Phospholipids and Glycosphingolipids in
Clinical Medicine
Pulmonary Surfactant Metabolism and
Respiratory Distress Syndrome
Pulmonary surfactant
is a complex of lipids and proteins
with unique surface active properties that is synthe-
sized exclusively in alveolar type II cells. The compo-
sition of surfactant is 90% lipids and 5-10% surfactant-
specific proteins. The lipid component is made up of
dipalmitoylphosphatidylcholine
(also
called
lecithin,
70-80%) and another major phospholipid, phosphatidyl-
glycerol (PG,
10%). The remainder of the phospho-
lipids of surfactant are phosphatidylinositol (PI), phos-
phatidylethanolamine (PE), and phosphatidylserine (PS).
Immature surfactant contains higher amounts of PI com-
pared to PG. Thus, a low ratio of PG to PI indicates lung
immaturity. Cholesterol, a neutral lipid, is also a con-
stituent of the lipid component of surfactant.
