Galactosylceramide (GalCer, cerebroside) has been discovered at the end of the nineteen’s 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.
‘In commemoration of the many enigmas which it presents to the inquirer’, Thudichum called it ‘sphingosine’ (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 - don’t 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.