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
- The gene on chro-
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
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.
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
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
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
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
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
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
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
G a l
d e s ia lo
d e s ia lo -
L a c -C e r
F I G U R E 1 9 -8
Degradative pathways for glycosphingolipids. Gm
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
—s- 4) glucose]; Cer =
ceramide (N-acylsphingosine,); desialo = without a sialic acid (NANA)
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