gangliosides
GANGLIOSIDES
Gangliosides are the group of glycosphingolipids
that show the greatest structural variation and also the more complex structure.
Except some echinoderms, gangliosides are characteristic of vertebrate nervous
tissues.
These glycosphingolipids were discovered and named by Ernst Klenk ( Z Physiol Chem
1942, 273, 76) after their isolation from brain tissue (they account for about 6% of
the lipid weight). Klenk identified sphingosine, fatty acid, hexose and a substance, which
was called neuraminic acid, and which gave a purple color with Bial's reagent. This acid
was later identified to be the same compound as the sialic acid isolated by Blix from
mucin. Other investigators have since found these lipids on all cell membranes in all
tissues. The heterogeneity of the brain ganglioside fraction was first shown by
Svennerholm in 1956 (Nature 1956, 177, 524). A typical ganglioside is shown
below, referred to as GM1 according to the adopted shorthand nomenclature (Svennerholm,
Comprehensive biochemistry, vol 18, Elsevier, 1970).
This group includes molecules composed of
ceramide linked by a glycosidic bond to an oligosaccharide chain containing hexose and
N-acetylneuraminic acid (NANA, acidic sugar known also as sialic acid) units.
Below is recalled the structure of the most important gangliosides found in nervous tissue and other locations.
The Svennerholm shorthand is used
(on the right part) where G is for ganglioside, M for monosialo-, D for disialo- and T for
trisialo-ganglioside. Cer,
ceramide; Glc, glucose; Gal, galactose; GalNAc, N-acetyl galactosamine; NANA, sialic acid;
the number 1, 2 or 3 characterizes the carbohydrate sequence.
The principles of the ganglioside-synthesizing machinery has been reviewed (Kolter
T et al., J Biol Chem 2002, 277, 25859).
The major long-chain bases are sphingosines with 18 or 20 carbon atoms. The fatty acid is
in a large proportion stearic acid (about 90% in the brain). The main gangliosides of the
brain are GM1, GD1a, GD1b and GT1. GM3 is present mainly outside brain tissues.
In examining brain belonging to various vertebrate classes, it was found that
the ganglioside content roughly corresponds with increasing complexity of the
nervous system but that the ganglioside composition is strikingly reduced over
phyletic lines. Furthermore, lower vertebrates show only little variation in the
ganglioside pattern between the different brain structures, whereas in higher
vertebrates differences distinctly occurred (Hilbig R, Comp Biochem Physiol
1984, 77B, 151).
There exists abnormal conditions in which genetic defects in catabolism lead to
ganglioside accumulations. In generalized gangliosidosis, GM1 accumulates in the nervous
system leading to mental retardation and liver enlargement. GM2 accumulation can
result from inherited defects in either the hexosaminidase
a
or
b
subunit, or in the GM2 activator protein, leading to Tay-Sachs disease (B
variant), Sandhoff disease (O variant), or GM2 activator deficiency (AB
variant), respectively. These pathologies lead to mental retardation and blindness.
Gangliosides are characterized by a high amount of stearic acid (C18, about 80%), the rest
being C16, C20 and C22. They contain no hydroxy fatty acids.
GM3 was demonstrated to regulate the human EGF receptor by preventing the
autophosphorylation of the intracellular kinase domain in response to ligand
binding (Coskun
U et al., PNAS 2011, 108, 9044).
GD1a and GT1b were determined to be specific ligands for the myelin-associated
glycoprotein, complex which inhibits nerve regeneration (Vyas et al.,
PNAS 2002, 99, 8412). The knowledge of this mechanism may provide novel
approaches to enhance nerve regeneration after injury.
GD3 was shown to contribute to mitochondrial changes leading to apoptosis (De
Maria R et al., Science 1997, 277, 1652).
During apoptosis, GD3 is rapidly synthesized from ceramide by a sialyltransferase resident in
the Golgi, the GD3 synthase; then, it relocates to mitochondria where it
contributes to the opening of the mitochondrial permeability transition pore
complex, with consequent release of apoptogenic factors (Mallisan
F et al., Biochim Biophys Acta 2002, 1585, 179).
Anti-ganglioside antibodies were first detected in the serum of patients with
the autoimmune neuropathy called
Guillain�Barr� syndrome in 1988 (Ilyas
AA et al., Ann Neurol 1988, 23, 440). Evidence to support their
importance has grown over several decades, including clinical�serological
studies and animal models. Various aspects of these interactions have been
reviewed (Rinaldi
S et al., Prog Lipid Res 2010, 49, 87).
9-O-Me-NeuGca(2-11)-9-O-Me-NeuGca(2-11)-9-O-Me-NeuGca(2-3)-Ins-1-P-Ceramide
The ceramide moiety was shown to contain C16 sphingosine and C22:0-C24:0 fatty acid. Furthermore it exhibited neuritogenic activity in the presence of nerve growth factor.
An unusual GM2 derivative, taurine-conjugated GM2, (tauro-GM2),
has been described in brain samples from patients with Tah-Sachs disease (Li
YT et al., J Biol Chem 2003, 278, 35286). The structure of that novel
ganglioside was established to present the carboxyl group of N-acetylneuraminic
acid amidated by taurine (see below).
The presence of tauro-GM2 in Tay-Sachs
brains, but not in normal brains, indicates the possible association of this
compound with the pathogenesis of that disease. As the amount of GM2 is largely
increased (from 20 up to about 1000 nmol/g wet brain tissue), neural tissues may
contend with this highly concentrated GM2 in
using taurine conjugation as a mean to remove the excess
of GM2 but in accumulating a new compound with possible toxic surfactant
properties.
Unique gangliosides have been described in echinoderms (sea urchin, starfish).
Curiously, these gangliosides contain in sea urchin, besides sialic acid, only
glucose as sugar component. Furthermore, sialic acid is internally situated or
bound to the terminal glucosyl group. A review of these glycosphingolipids in
echinoderms may be found by T Hori et al (Prog Lipid Res 1993, 32, 25).
