Chemistry Reference
In-Depth Information
latter is found to a limited extent in the nervous system and elsewhere, and is
distinguished from GM1a in its susceptibility to sialidase and nonreactivity toward
cholera toxin B-subunit (see below). In contrast to the numerous defects in GSL
catabolic enzymes (see below), there is a paucity of reports on inborn errors of
synthetic enzymes. One such report [7] describes an infantile- onset symptomatic
epilepsy syndrome due to mutation of GM3 synthase with resultant absence of
gangliosides of the a-, b- and c-series (Figure 30.3; for more information on this
disorder, please see Chapter 22.7 ).
Glycohydrolases responsible for catabolic metabolism also progress one sugar
at a time, in a manner formally analogous to reversal of the synthetic reactions of
Figure 30.3; however, the relevant catabolic enzymes are quite distinct from those
in the synthetic pathways and reside largely in lysosomes (please see also Chapter
10). Failure of specifi c glycosidase activities due to genetic mutations gives rise
to lysosomal storage disorders such as the gangliosidoses [8]. The fi rst of these
to be biochemically characterized was Tay-Sachs disease (GM2 gangliosidosis),
eventually shown to result from mutation of the gene for the
α
- subunit of
β
-hexosaminidase A that cleaves GalNAc from GM2 in normal brain (Table 30.1 ).
GM2 is a convergent product in metabolism of the a- , b - and c - series gangliote-
traose gangliosides (please see also Chapter 10), and several known mutations
result in GM2 accumulation in lysosomal storage vesicles leading to neuronal
destruction and usually early death. The O variant (Sandhoff's disease) results
from mutation in the gene for the
β
- subunit,
thereby
inactivating
both
β
). Finally, the AB variant arises from defects
in the gene for the GM2 activator, a necessary cofactor for
- hexosaminidase A (
α
β
) and B (
β
β
- hexosaminidase activ-
ity; the latter enzyme is normal in these patients when supplemented with the
activator. GM1 gangliosidosis results from neuronal accumulation of GM1 due to
an inherited defect of GM1
β
-galactosidase. There are clinically distinct forms of
this disorder (Table 30.1), some due to mutation of the galactosidase itself and
another to mutation in the protective protein that protects
β
- galactosidase and an
associated sialidase from premature proteolytic degradation. Many mutations have
been found in both
β
- galactosidase, the form and severity
of the disease correlating with residual enzyme activity.
Sialidase (neuraminidase) catalyzes removal of terminal sialic acid residues
from gangliosides and glycoproteins, often with resultant infl uence on cellular
activity. Four genetically distinct forms of mammalian sialidase have been cloned
and characterized, each with a predominant cellular localization and substrate
specifi city [5]. Neu3 is associated with the plasma membrane and shows preferen-
tial reactivity toward gangliosides [9]. This enzyme converts oligosialogangliosides
of the a- , b - and c -series to GM1, whose sialic acid resists hydrolysis, and this exerts
a regulatory role on neuronal differentiation and transformation in neuroblastoma
cells [10] (please see Chapter 25 for the functional role of the GM1- lectin interac-
tion) as well as primary neurons [11]. Such observations point up the signifi cance
of GM1 in neuronal process outgrowth, related at least in part to its infl uence on
calcium regulatory mechanisms in addition to its effect on neurotrophic receptors
(see below); GM2 and GM3 also infl uence Ca
2+
regulation in some cells [12] . Neu1
β
- hexosaminidase and
β
