Sphingomyelin cycle (ceramide <-> sphingomyelin interconversion)

Sphingomyelin (SM) is the most abundant sphingolipid of the plasma membrane and a defining component of lipid rafts and the myelin sheath. The "sphingomyelin cycle" is the reversible interconversion of SM and ceramide, which couples membrane-lipid homeostasis to ceramide/diacylglycerol signalling. In the synthetic direction the sphingomyelin synthases SGMS1 (trans-Golgi) and SGMS2 (plasma membrane) transfer a phosphocholine head group from phosphatidylcholine (PC) to ceramide, producing SM + diacylglycerol (DAG) — simultaneously consuming the pro-apoptotic lipid ceramide and generating the pro-mitogenic lipid DAG. In the hydrolytic direction, sphingomyelinases (SM phosphodiesterases) cleave SM back to ceramide + phosphocholine, generating the ceramide second messenger. Human cells use several, distinguished by pH optimum and location: the lysosomal acid sphingomyelinase SMPD1 (turnover and the ASMase/ceramide stress pathway; Niemann-Pick A/B on deficiency), and the Mg2+-dependent neutral sphingomyelinases SMPD3 (nSMase2, the major stress-responsive plasma-membrane/Golgi enzyme controlling ceramide signalling, exosome secretion and bone mineralization), SMPD4 (nSMase3, ER/Golgi/nuclear-envelope) and SMPD2 (nSMase1, ER; note its preferred cellular substrate is lyso-platelet-activating factor, so its bulk-SMase role is limited). The ceramide produced feeds the ceramidase/sphingosine-1-phosphate rheostat and re-acylation pathways. Inherited defects illustrate the pathway: SMPD1 Niemann-Pick disease, SGMS2 and SMPD3 skeletal dysplasias, and SMPD4 a neurodevelopmental disorder with microcephaly.