Involving Sphingolipids

There are a number of recent reviews of the sphingolipidoses such as those of van Bogaebt et al., 1957 Volk and Spebby, 1959 Stanbuby et al., 1960 Folch-Pi, 1961 Abonson and Volk, 1962 and Folch-Pi and Baueb, 1963. The following selectively document the known sphingolipid storage diseases with newer references and mention briefiy several recent observations. 

Agranoff, B. W., N. Rad in, and W. Suomi Enzymic oxidation of cerebrosides studies on Gaucher s disease. Biochim. biophys. Acta (Amst.) 67,194 (1962). 

Aminoff, D., F. Dodyk, and S. Roseman Enzymatic synthesis of colominic acid. J. biol. Chem. 238, 1177 (1963). 

Aronson, S. M., and B. W. Volk Cerebral Sphingolipidosis. New York Academic Press, Inc. 1962. 

---

Table II. Genetic Lipid Storage Diseases Involving Sphingolipid Hydrolysis ...

At least three lipid metabolic networks and their relationships, which are common and essential to the majority of the lipids in mammals and plants, should be recognized. These networks include the one involving sphingolipid metabolism, the one related to GPL metabolism, and the one for glycerolipids. 

Phospholipids Sphingolipids Are Involved in Multiple Sclerosis and Lipidoses... 

Phospholipids and sphingolipids are involved in several disease processes, including respiratory distress syndrome (lack of lung surfactant), multiple sclerosis... 

While the fluid mosaic model of membrane stmcture has stood up well to detailed scrutiny, additional features of membrane structure and function are constantly emerging. Two structures of particular current interest, located in surface membranes, are tipid rafts and caveolae. The former are dynamic areas of the exo-plasmic leaflet of the lipid bilayer enriched in cholesterol and sphingolipids they are involved in signal transduction and possibly other processes. Caveolae may derive from lipid rafts. Many if not all of them contain the protein caveolin-1, which may be involved in their formation from rafts. Caveolae are observable by electron microscopy as flask-shaped indentations of the cell membrane. Proteins detected in caveolae include various components of the signal-transduction system (eg, the insutin receptor and some G proteins), the folate receptor, and endothetial nitric oxide synthase (eNOS). Caveolae and lipid rafts are active areas of research, and ideas concerning them and their possible roles in various diseases are rapidly evolving. 

The distinguishing structural and functional protein for caveolae is caveolin. Caveolin proteins display properties that are likely involved in the distinguishing morphology of caveolae. Caveolins have a high affinity for both cholesterol and sphingolipids coupled with 3 carboxy-terminal palmitoylated cysteine residues. Three isoforms of caveolin exist and show distinct tissue distribution. Likely because it was discovered first and is perhaps most abundant, caveolin-1 has garnered the lion s share of research attention. 

Vitamin B6 occurs naturally in three related forms pyridoxine (6.26 the alcohol form), pyridoxal (6.27 aldehyde) and pyridoxamine (6.28 amine). All are structurally related to pyridine. The active co-enzyme form of this vitamin is pyridoxal phosphate (PLP 6.29), which is a co-factor for transaminases which catalyse the transfer of amino groups (6.29). PLP is also important for amino acid decarboxylases and functions in the metabolism of glycogen and the synthesis of sphingolipids in the nervous system. In addition, PLP is involved in the formation of niacin from tryptophan (section 6.3.3) and in the initial synthesis of haem. 

Synthesis of plasmalogens involves formation of their characteristic double bond by a mixed-function oxidase. The head groups of sphingolipids are attached by unique mechanisms. 

The enzymes involved in the synthesis of glycosphingolipids are cjh cosyl transferases, each specific for a particular sugar-nucleotid and acceptor. [Note These enzymes may recognize both glya sphingolipids and glycoproteins as substrates.]... 

Conformational restriction of biologically flexible molecules is a successful strategy in drug development. Application of this concept to ceramide, the membrane anchor of sphingolipids, led to the unexpected inhibition of glycosyltransferases involved in the combinatorial biosynthesis of gangliosides. This discovery offers a new approach to cell surface engineering. 

---