The Organizing Potential of Sphingolipids in Intracellular Membrane ...

1692 HOLTHUIS, POMORSKI, RAGGERS, SPRONG, AND VAN MEER
accompanies functional differences between the various
cell types of an animal. Whereas the synthesis of at least
some glycosphingolipid species appears essential for the
viability of animal organisms (see sect. IIB), as a lipid
class they are dispensable for the growth and survival of
animal cells in culture. This is not the case for phosphosphingolipids.
Phosphosphingolipid synthesis is required
for cell growth and survival, in yeast as well as in mammals
(the only organisms in which this has been studied
so far). Yeast and Chinese hamster ovary cell mutants
lacking the first committed enzyme in sphingolipid biosynthesis,
serine palmitoyl-transferase (Fig. 2), die in the
absence of externally added sphingoid base (123, 411).
The mammalian mutant could be rescued by exogenous
SM, but not by glucosylceramide (GlcCer), the precursor
of higher glycosphingolipids (121, 123). It therefore appears
that SM, and not GlcCer (or higher glycosphingolipids),
fulfills a vital role in mammalian cells. Indeed,
Physiol Rev • VOL 81 • OCTOBER 2001 • www.prv.org
FIG. 2. Pathways of ceramide synthesis.
Known metabolic intermediates, substrates,
and enzymes are indicated.
Names of genes whose products are required
for specific steps in yeast ceramide
synthesis are shown in italics and
discussed in section VA. Note that it remains
to be established whether C 4-hydroxylation
occurs on the free sphingoid
base (sphinganine) or on ceramide.
mammalian cell lines unable to synthesize GlcCer are
viable and proliferate (145). The alternative monoglycosylceramide,
galactosylceramide (GalCer), is not required
for cell survival either, since it is absent from most mammalian
cell types including the GlcCer-negative cells
(145).
Collectively, these observations raise two major
questions. What vital function do phosphosphingolipids
serve in the cell? And for what purpose do animal cells
create so many different types of glycosphingolipids in
addition, given that, in principle, they can live without
them? Complete answers to these questions are still
lacking. However, experimental work over the last decade
has indicated that cells exploit both chemical and
biophysical characteristics of sphingolipids to accomplish
some of their most fundamental tasks. Before
exploring which of these characteristics account for
the sphingolipid requirement in cell growth and sur-