De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway.

Much has been made about J. L. W. Thudichum’s colorful, and one could say clairvoyant, naming of sphingosine “in commemoration of the many enigmas which it presented to the inquirer” in his 1884 treatise The Chemistry of the Brain(1) because many of the riddles of sphingolipids (as the broader field was later named)(2) remained unanswered for the following century. This changed radically over the past several decades as researchers explored, and ultimately established, what seemed at the time to be radical concepts: that sphingolipids are not just structural elements of cells but also participate in intra- and extracellular signaling; that not only the complex glycan headgroups, but also the lipid backbones, are highly specified metabolically and have selective biochemical functions; and that even the longest known function of these lipids, as structural components of the “fluid mosaic” of cell membrane lipids, is not so simple, and often involves the dynamic clustering of sphingolipids in nontraditional microdomains referred to as rafts. We still know only a fraction of their secrets, but this enlightenment has defined models for thinking about these compounds that remove them from their enigmatic “black box.”

Now, a major challenge is to keep up with the rapid growth in knowledge about the sphingolipidome, that is, the ensemble of all sphingolipids.(3) A major goal of the review is to help the reader more easily grasp the metabolic interrelationships that account for the tens of thousands of molecular subspecies (and perhaps more) that appear in nature, with a focus on mammals. The magnitude of this subject precludes the inclusion of all of the enzymes and metabolites, and the author apologizes for the omission of many interesting topics. To put this information in context, there is a brief background discussion of their structures and functions, which have been dealt with also in a recent Chemical Reviews article(4) on the chemicophysical features of sphingolipids and raft formation, and by excellent reviews on sphingolipid signaling5,6 and the biological functions of complex glycosphingolipids.7−10

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

Eukaryotic organisms as well as some prokaryotes and viruses contain sphingolipids, which are defined by a common structural feature, i.e. , a "sphingoid base" backbone such as D-erythro-1,3-dihydroxy, 2-aminooctadec-4-ene (sphingosine). The sphingolipids of mammalian tissues, lipoproteins, and milk include ceramides, sphingomyelins, cerebrosides, gangliosides and sulfatides; plants, fungi and yeast have mainly cerebrosides and phosphoinositides. The total amounts of sphingolipids in food vary considerably, from a few micromoles per kilogram (fruits) to several millimoles per kilogram in rich sources such as dairy products, eggs and soybeans. With the use of the limited data available, per capita sphingolipid consumption in the United States can be estimated to be on the order of 150-180 mmol (approximately 115-140 g) per year, or 0.3-0.4 g/d. There is no known nutritional requirement for sphingolipids; nonetheless, they are hydrolyzed throughout the gastrointestinal tract to the same categories of metabolites (ceramides and sphingoid bases) that are used by cells to regulate growth, differentiation, apoptosis and other cellular functions. Studies with experimental animals have shown that feeding sphingolipids inhibits colon carcinogenesis, reduces serum LDL cholesterol and elevates HDL, suggesting that sphingolipids represent a "functional" constituent of food. Sphingolipid metabolism can also be modified by constituents of the diet, such as cholesterol, fatty acids and mycotoxins (fumonisins), with consequences for cell regulation and disease. Additional associations among diet, sphingolipids and health are certain to emerge as more is learned about these compounds.

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Sphingolipids in Food and the Emerging Importance of Sphingolipids to Nutrition

Ceramides and other bioactive sphingolipid backbones in health and disease: Lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy

Karl-Anders Karlsson

Papers

On the chemistry and occurrence of sphingolipid long-chain bases.