History
Galactosylceramide
(GalCer, cerebroside) has been discovered at the end of the nineteenÕs century
by J.L.W. Thudichum,
the pioneer in the chemistry of the brain (1). He
coined the term cerebrosides for a group of glycosidic substances found in
brain and composed of three building blocks : a fatty acid, a long chain base, and a
hexose. The sugar obtained by hydrolysis of the crude product was called cerebrose,
so that the name cerebroside was chosen in analogy of the plant glycosides. In
1874, Thudichum isolated cerebrosides as an impure fraction consisting of two
principal species, i.e. phrenosin and kerasin, that differed structurally by
their fatty acid component only (2) and
physically by their optical activity (phrenosin is dextrorotatory, kerasin
levorotatory). Forty years later, Thierfelder showed that phrenosin contains a
long chain α-hydroxy fatty acid, and that the acid of kerasin is lignoceric
acid, i.e. CH3-(CH2)22-COOH (3). He also identified the sugar component as
galactose. Yet the structure of the third building block, i.e. the long chain
base, remained elusive for almost fifty more years.
ÔIn commemoration of the many enigmas
which it presents to the inquirerÕ, Thudichum called it ÔsphingosineÕ (in
reference to the Sphinx enigmas). Sphingosine can be easily obtained from an
alkaline hydrolysate of phrenosin. Its correct structure was established by
Carter et al. (4) in 1947. In 1958, D. Shapiro et al. published the
total synthesis of sphingosine, confirming its chemical structure as trans-D-erythro-1,3-dihydroxy-2-amino-4-octadecene
(or, according to the R/S system, trans-(2S,3R)-1,3-dihydroxy-2-amino-4-octadecene
(5). In practical, it is a C18 carbon chain (CH3-(CH2)16-CH3),
with two OH groups (at positions 1 and 3 from a terminal CH3 - donÕt worry
which one, you select one when you write the structure
-), one amino group (at position 2), and a C4-C5 trans double bond. It is amazing that such a simple molecule has
resisted for decades to several generations of talented biochemists !
Carter
et al. have also introduced the term sphingolipids to designate lipids derived
from the parent base sphingosine.
Now
why is cerebroside also called galactosylceramide ? For several
reasons :
In the central nervous system, GalCer is a major lipid constituent of myelinating oligendrocytes, consistent with its high content in myelin (7). It is also present in neurons, particularly in axons. Not surprisingly, chronic impairments of GalCer biosynthesis and/or degradation can cause severe illness. GalCer is also highly expressed in several epithelial tissues such as the mucosal intestinal epithelium, where it may promote the adhesion of various pathogens, including HIV and prions. To understand the biological function(s) of GalCer, you should first be more familiar with its chemical structure, which determines its unique physicochemical properties. In the following section, you will learn how to draw correctly a GalCer molecule.