Small differences equal big results

Insights into sphingolipid structural variants

Since the discovery of sphingolipids in the late 1800s, scientists have made a lot of progress in characterizing some of the diverse interactions and functions carried out by these often complex and enigmatic molecules. However, given the sheer number of these molecules, it seems likely that there are even more interactions waiting to be discovered. The Journal of Biological Chemistry’s recent thematic minireview series “ Novel Bioactive Sphingolipids” focuses on three structural variants, their functions and their intriguing therapeutic potential.

In the first article, authors Mitchell Kronenberg at La Jolla Institute for Allergy and Immunology and colleagues focus on the relationship between natural killer T cells (called NKT cells for short) and glycosphingolipids. The authors write about known glycosphingolipid structural variations, especially compounds with a novel alpha-glycosidic linkage, and how these have been shown to vary the immune response that occurs upon NKT cell activation. Of specific interest is these molecules' capability of producing different types of immune responses, including both anti- and pro-inflammatory responses. Though the field remains controversial, it seems a major factor in determining the type of response is the amount of time the antigen is available to the T-cell receptor. The authors discuss potential mechanisms for determining which type of immune response is induced, pointing out that the binding affinity between the lipid and CD1b, the cell-surface molecule that presentsthe lipid to T-cell receptors, appears to be particularly important. The authors also mention the prevalence of glycosphingolipids in both microbes and mammalian cells, indicating they may play a role in microflora and immune-system development. Ultimately, because of the glycosphingolipids' ability to produce contrasting immune responses, the authors posit that they may have clinical roles as immune-modulating agents. 

But it’s not only the end products of sphingolipid synthesis that hold potential therapeutic applications. Though originally thought to be nonfunctional intermediates, the dihydroceramides, the subject of the second review in the series, also have proved to have important functional roles. Scott Summers and colleagues at the Baker IDI Heart and Diabetes Institute in Australia note  that dihydroceramides previously were believed to be rare. But recently these intermediates were found to be increased in a variety of conditions, including autophagy, hypoxia and, more controversially, apoptosis. Interestingly, this increase is correlated with inhibited cell proliferation, an effect most likely brought about by the oxygen-dependent function of the dihydroceramide desaturases. Responsible for the insertion of a double bond that converts dihydroceramide to ceramide, these enzymes likely are behind many of the biologic effects related to dihydroceramide levels. Indeed, numerous drugs that interfere with dihydroceramide desaturase function also decrease cell proliferation. Moreover, these regulatory aspects indicate the potential role of dihydroceramide desaturases in numerous diseases, including cancer, periodontal disease, AIDS and metabolic disorders.

The mysteries of sphingolipids don’t stop there. Recently, scientists identified strange structural variants capable of producing uncommon effects. In the final minireview of the series, authors Jingjing Duan and Alfred H. Merrill Jr. at the Georgia Institute of Technology explore yet another sphingoid structural variant, the deoxysphingolipids. Though scientists are only beginning to elucidate the biology of these molecules, the deoxysphingolipids already are known to influence numerous cellular processes. For example, they have potent effects on cell growth and survival. Initially studied because some have potent cytotoxic effects believed to serve as defense mechanisms for some fungi, these molecules also have been found in mammals, including humans. Not only that, but these molecules also have been correlated with several illnesses, including neurologic disorders, diabetes and liver disease. There even have been a few clinical trials with deoxysphingoid base analogs. Learning more about these structural variants will reveal more therapeutic possibilities.

We often are tempted in this new age of -omics to assume we know all of the answers, but small differences in structure can make big differences in function. Though we know a lot about the sphingolipids, we have much more to learn, and intriguing evidence continues to highlight new and important potential roles for these mysterious molecules.

Bree Yanagisawa Bree Yanagisawa is a graduate student at the Johns Hopkins School of Medicine and managing editor of the Biomedical Odyssey blog.