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, (215), 57-76

Sphingolipid Metabolism and Neutral Sphingomyelinases


Sphingolipid Metabolism and Neutral Sphingomyelinases

Michael V Airola et al. Handb Exp Pharmacol.


Sphingolipids are an important class of lipid molecules that play fundamental roles in our cells and body. Beyond a structural role, it is now clearly established that sphingolipids serve as bioactive signaling molecules to regulate diverse processes including inflammatory signaling, cell death, proliferation, and pain sensing. Sphingolipid metabolites have been implicated in the onset and progression of various diseases including cancer, lung disease, diabetes, and lysosomal storage disorders. Here we review sphingolipid metabolism to introduce basic concepts as well as emerging complexities in sphingolipid function gained from modern technological advances and detailed cell and animal studies. Furthermore, we discuss the family of neutral sphingomyelinases (N-SMases), which generate ceramide through the hydrolysis of sphingomyelin and are key enzymes in sphingolipid metabolism. Four mammalian N-SMase enzymes have now been identified. Most prominent is nSMase2 with established roles in bone mineralization, exosome formation, and cellular stress responses. Function for the other N-SMases has been more enigmatic and is an area of active investigation. The known properties and potential role(s) of each enzyme are discussed to help guide future studies.


Figure 1
Figure 1. Sphingolipid metabolism and chemical structure
(A) Diagram of sphingolipid metabolism showing the major lipid species in grey boxes and sphingolipid metabolizing enzymes. The number of mammalian genes that catalyze each conversion are denoted by brackets. (B) Generic structure for sphingolipid molecules with modification points. The presence or absence of the acyl chain (lower chain) distinguishes ceramide (shown) from sphingosine. Variation in the headgroup (1), attached to the terminal 1-oxygen, distinguishes each family of sphingolipids. The length of the sphingoid backbone (4) or acyl-chain (2) generates subspecies within each family. Further modification at the 4,5 position on the sphingoid backbone (3) can occur with different saturation levels (e.g. dihydroCer vs. Cer) and hydroxylation. In addition, the acyl chain can be hydroxylated at the 2-position (5). Abbreviations: SPT = serine phosphoryltransferase, CerS = (dihydro)ceramide synthase, DES = dihydroceramide desaturase, SMase = sphingomyelinase, SMS = sphingomyelin synthase, CerK = ceramide kinase, GBA = glucosylceramidase, GALC = galactosylceramidase, GCLT = ceramide glucosyltransferase, CGT = ceramide galactosyltransferase, CDase = ceramidase, SK= sphingosine kinase, SPP = S1P-phosphatase.
Figure 2
Figure 2. Domain architecture and topology of N-SMase isoforms
(A) Domain architecture of N-SMase isoforms highlighting the catalytic domain, membrane-associated or transmembrane regions, and sites of protein binding or post-translational modifications. (B) nSMase2 contains two domains: an N-terminal domain with two hydrophobic segments (HS1 & HS2) that associate with but do not span the membrane and a C-terminal catalytic domain (blue). For the catalytic domain, the structure of a bacterial homologue (bSMase, PDB: 2DDR) is shown with the active site towards the membrane. (C) Sphingomyelinases catalyze the hydrolysis of SM to generate Cer and phosphocholine.

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