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chapter 19
Lipids II: Phospholipids, Glycosphingolipids, and Cholesterol
of the molecule. Each sugar residue removed involves a
specific exoglycosidase. Sulfatases are required for the
removal of sulfate groups from sulfolipids. The degrada-
tion of sphingolipids, in addition to their requirement for
specific hydrolases, is also dependent on nonenzymatic
glycoproteins, known as
sphingolipid activator proteins
(SAPs). SAP-stimulated degradation of sphingolipids is
thought to involve the binding of the activator protein with
the sphingolipids so that the water-soluble hydrolases can
access the specific sites of hydrolysis. Genes for SAPs
are located in chromosomes 5 and 10. The SAP gene that
resides in chromosome 5 codes for the activator of hex-
oseaminidase A, which hydrolyzes Gm
2
- The gene on chro-
mosome
1 0
codes for a precursor which, after synthesis in
the endoplasmic reticulum, is exported to the cell surface
followed by its importation into the lysosomal compart-
ment. In the lysosomes, the precursor protein is processed
to yield four mature activator proteins: sap-A, sap-B,
sap-C, and sap-D. The activator function of these proteins
are as follows: sap-A stimulates glucosylceramidase and
galactosylceramidase in the presence of detergents; sap-B
is a nonspecific activator that stimulates hydrolysis of
about
2 0
glycolipids as well as hydrolysis of sulfatide
by arylsulfatidase A; sap-C is essential for the action of
glucosylceramidase; and function of sap-D is unknown.
The importance of SAPs is exemplified in disorders
where these activator proteins are not made as a result
of mutations. A defect in the synthesis of the enzyme or
its activator protein can both result in the same pheno-
type. Examples are hexoseaminidase A deficiency or its
activator protein (Ganglioside G
M 2
activator) resulting in
Tay-Sachs d ise a se
; arylsulfatase A deficiency or its acti-
vator protein sap-B resulting in
ju ven ile m etachrom atic
leukodystroph y,
and glucosylceramidase deficiency or its
activator protein sap-C resulting in
G a u ch er’s disease.
All
of these disorders are accompanied by pronounced accu-
mulation of the respective precursor lipids in the retic-
uloendothelial system. Sphingomyelin is hydrolyzed to
ceramide and phosphorylcholine by sphingomyelinase:
Sphingomyelin + H
2
O
—*■
phophorylcholine + ceramide
Deficiency of sphingomyelinase leads to
N iem an-P ick
d isea se
A and B in which sphingomyelin accumulates
in reticuloendothelial cells, peripheral tissues, and cen-
tral nervous system and affects all of these tissues and
organs.
N iem an-P ick d isea se C
(and D) has normal tissue
sphingomyelinase levels but exhibits defects in intracellu-
lar trafficking of exogenous cholesterol leading to lysoso-
mal unesterified cholesterol accumulation. The C variant
is characterized by hepatic damage and neurologic dis-
ease. Each of these disorders is inherited as an autosomal
recessive trait.
Ceramide is hydrolyzed to sphingosine and fatty acid
by ceramidase:
Ceramide + H
2
O —►
sphingosine + fatty acid
A nonlysosomal ceramidase in some tissues functions op-
timally at neutral or alkaline pH and participates in the
synthesis and breakdown of ceramide. Deficiency of lyso-
somal (acid) ceramidase in
F a rb er’s d isea se
(lipogranu-
lomatosis) causes accumulation of ceramide. The disease
is inherited as an autosomal recessive trait and is charac-
terized by granulomatous lesions in the skin, joints, and
larynx and moderate nervous system dysfunction; it may
also involve heart, lungs, and lymph nodes. It is usually
fatal during the first few years of life.
Sphingosine is catabolized to trans-2-hexadecanal and
phosphoethanolamine by way of sphingosine phosphate
and its cleavage by a lyase. Catabolism of glycosphin-
golipids involves removal of successive glycosyl residues
from their nonreducing end until ceramide is released.
Abnormalities usually
involve
specific exoglycosi-
dases and their activator proteins (discussed earlier) that
hydrolyze the glycosidic bonds, except in metachro-
matic leukodystrophy, in which there is deficiency of a
sulfatidase.
Catabolic pathways for the glycosphingolipids are given
in Figure 19-8 and associated disorders are summarized
in Table 19-1. Some comments are warranted:
G a l
N A c G a l
NAN A
G a l
d e s ia lo
d e s ia lo -
N A N A
L a c -C e r
F I G U R E 1 9 -8
Degradative pathways for glycosphingolipids. Gm
1
,
2,3
arc gangliosides.
Their structures and those of globosides and sulfatides should be inferred
from their respective catabolic routes. The circled numbers correspond to
the metabolic lesions listed in Table 19-1. Gal = Galactose; Glc = glucose;
NAcGal = N-acetyl-galactose-2-amine; NANA = N-acetyl neuraminic
acid (a sialic acid); Lac = lactose [galactosyl
(ft
-1
—s- 4) glucose]; Cer =
ceramide (N-acylsphingosine,); desialo = without a sialic acid (NANA)
residue.
