What Are Sphingolipids?
Sphingolipids are the most structurally diverse class of membrane lipids, being composed of over 70 long-chain (sphingoid) bases, dozens of amide-linked fatty acids, and more than 300 headgroups. Sphingolipids are present in all eukaryotic and some prokaryotic organisms.
1.What Is The Function Of A Sphingolipid?
Sphingolipids are highly bioactive compounds that participate in the regulation of cell growth, differentiation, diverse cell functions, and apoptosis. Sphingolipids are both structural and functional lipids. Their physical properties (such as high phase transition temperatures) affect the properties of membranes and lipoproteins, and they are critical components of the water barrier of skin. Besides, they serve as ligands for extracellular matrix proteins and receptors on neighboring cells, as well as for enteric bacteria and viruses. Sphingolipids are also important in cell regulation as modulators of growth factor receptors and as second messengers for a growing list of agonists (including tumor necrosis factor-α, interleukin-1β, nerve growth factor and 1α, 25-dihydroxyvitamin D3).
2.Where Are Sphingolipids In The Body?
Sphingolipids are found throughout the body. They are mainly located in nerve cell membranes and account for about 25% of the lipids in the myelin sheath. First found in brain tissue, some sphingolipid subgroups can be found in other parts of the body, including the spleen and blood.
3.What Are The Major Types Of Sphingolipids?
Depending on the modifying structures, sphingolipids are classified into sphingomyelins and glycosphingolipids. Sphingomyelins consist of phosphocholine or phosphoethanolmine and ceremide. Glycosphingolipids include cerebrosides, sulfatides, globosides, and gangliosides with carbohydrate groups attached to the 1-OH position of sphingosine. Cerebrosides contain a mono sugar group (galactose or glucose) and ceremide. Galactocerebroside is primarily present in neuronal cell membranes.
4.What Are Sphingolipid-Based Drugs?
Sphingolipids have a significant role as structural components in cell membranes as well as signaling molecules in regulatory pathways, such as cell cycle arrest, apoptosis, senescence, and differentiation. With these roles, sphingolipids and sphingolipid synthesis emerge as a logical target for drug development, with the majority of the thus-far tested drugs targeting enzymes that are involved in the production of various sphingolipid subtypes.
The goal of these novel therapies is to adjust the sphingolipid metabolism so as to accumulate ceramine and to decrease sphingosine-1-phosphate, which is a tumor-promoting lipid. The target enzymes of human sphingolipid pathway are serine palmitoyl transferase, ceramine synthase, ceramidase, sphingosine kinase, glucosylceramide synthase, and 1-O-acylceramide synthase. Several drugs targeting these enzymes, including 4-HPR, PSC 833, daunorubicin, B13, safingol, PPMP, PPPP, butyldeoxynojiriMYCin and phenoxodiol, are currently in preclinical or clinical trials.
To date, the drugs taken in general to target sphingolipid metabolism for cancer therapy have involved: (a) synthetic ceramide analogs; (b) small-molecule inhibitors of enzymes that catabolize ceramide; (c) the inhibitor of SK; and (d) S1P receptor antagonists.
References
1.Merrill Jr, Alfred H., et al. Importance of sphingolipids and inhibitors of sphingolipid metabolism as components of animal diets. The Journal of nutrition. 1997, 127(5):830S-3S.
2.Garg U, Smith LD. Biomarkers in Inborn Errors of Metabolism: Clinical Aspects and Laboratory Determination. Elsevier; 2017.
3.Karlsson KA. On the character and functions of sphingolipids. Acta biochimica Polonica. 1998, 45(2):429-38.
4.Čuperlović-Culf M. NMR metabolomics in cancer research. Elsevier; 2012.