Glycosphingolipids—Nature, Function, and Pharmacological Modulation

Abstract

The discovery of the glycosphingolipids is generally attributed to Johan L. W. Thudichum, who in 1884 published on the chemical composition of the brain. In his studies he isolated several compounds from ethanolic brain extracts which he coined cerebrosides. He subjected one of these, phrenosin (now known as galactosylceramide), to acid hydrolysis, and this produced three distinct components. One he identified as a fatty acid and another proved to be an isomer of D-glucose, which is now known as D-galactose. The third component, with an "alkaloidal nature", presented "many enigmas" to Thudichum, and therefore he named it sphingosine, after the mythological riddle of the Sphinx. Today, sphingolipids and their glycosidated derivatives are the subjects of intense study aimed at elucidating their role in the structural integrity of the cell membrane, their participation in recognition and signaling events, and in particular their involvement in pathological processes that are at the basis of human disease (for example, sphingolipidoses and diabetes type 2). This Review details some of the recent findings on the biosynthesis, function, and degradation of glycosphingolipids in man, with a focus on the glycosphingolipid glucosylceramide. Special attention is paid to the clinical relevance of compounds directed at interfering with the factors responsible for glycosphingolipid metabolism.

Acid ceramidase as a therapeutic target in metastatic prostate cancer

“…Ceramide may also be converted back to SM by transfer of phosphorylcholine from phosphatidylcholine via SM synthases ( 14 ). Alternatively, it can be glycosylated by glucosylceramide synthase to form glucosylceramide, which may be further modifi ed by various enzymes in the Golgi apparatus to form complex glycosphingolipids ( 15 ).…”

A search for ceramide binding proteins using bifunctional lipid analogs yields CERT-related protein StarD7

“…Sphingolipids are abundant components of eukaryotic membranes that participate in a wide array of cellular processes by modulating vital physical membrane properties and as signalling molecules in responses to physiological cues and stresses (1)(2)(3)(4). Notably ceramides, the central intermediates of sphingolipid metabolism, receive considerable attention as key mediators of anti-proliferative cellular responses including apoptosis, autophagy, cell cycle arrest and senescence (5)(6)(7).…”

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

“…GCS catalyzes the first step in the biosynthesis of glycosphingolipids, and its cellular activity modulates the levels of the other lipids as well as ceramide (7)(8)(9). Early studies demonstrated that increasing the capacity for ceramide glycosylation in GCS-transfected human breast cancer MCF-7 cells conferred greater resistance to doxorubicin and to TNF-· (10,11).…”