Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. (May 2016)

• Record Type: Journal Article
• Authors: Adada, Mohamad; Luberto, Chiara; Canals, Daniel
• Is Part Of: Chemistry and physics of lipids. Volume 197(2016)
• Page Start: 45
• Page End: 59
• Publication Date: 2016-05
• Subjects: alk-SMase alkaline sphingomyelinase -- aSMAse acid sphingomyelinase -- ATRA all-trans retinoic acid -- BMP bismonoacylglycerophosphate -- CAD cationic amphiphilic drugs -- CerS (dihydro)ceramide synthases -- D609 tricyclodecan-9-yl-xanthogenate -- DAG diacylglycerol -- IL interleukin -- L-aSMAse lysosomal-aSMase -- LCD lysosomal cell death -- LDLs low-density lipoproteins -- LPS ly–popolysaccharide -- Ma-nSMase mitochondrial associated nSMase -- MDR multidrug resistant -- NPD Niemman–Pick disease -- nSMase neutral sphingomyelinase -- PAF platelet-activating factor -- PC phosphatidylcholine -- PC-PLC phosphatidylcholine-specific phospholipase C -- PI phosphatidylinositol -- PLC phospholipase C -- PLD phospholipase D -- PM plasma membrane -- S1P sphingosine-1-phosphate -- S-aSMase secretory aSMAse -- SAP, sphingolipid activator protein -- SK sphingosine kinases -- SM sphingomyelin -- SMS sphingomyelin synthase -- SPT serine palmitoyl transferase -- TNF tumor necrosis factor -- TPA 12-O-tetradecanoyl-phorbol-13-acetate -- VLDLs very-low-density lipoprotein; Sphingomyelin -- Sphingomyelinase -- Sphingomyelinase synthase -- Ceramide -- Sphingolipids; Lipids -- Periodicals; Lipids -- Periodicals; Lipides -- Périodiques; Lipids; Periodicals; Electronic journals; 547.77
• DOI: 10.1016/j.chemphyslip.2015.07.008
• Languages: English
• ISSNs: 0009-3084

Abstract

Highlights: We summarized the history of the sphingolipid pathway focusing on the sphingomyelin cycle. We described the main biologic pathophysiologies involving sphingomyelin synthases and specific sphingomyelinases. We numbered, described and named examples of their use of the most used inhibitors for sphingomyelin synthases and sphingomyelinases. Abstract: Sphingolipids are a class of bioactive lipids, which are key modulators of an increasing number of physiologic and pathophysiologic processes that include cell cycle, apoptosis, angiogenesis, stress and inflammatory responses. Sphingomyelin is an important structural component of biological membranes, and one of the end-points in the synthesis of sphingolipids. Mainly synthetized in the Golgi apparatus, sphingomyelin is transported to all other biological membranes. Upon stimulation, sphingomyelin can be hydrolyzed to ceramide by 5 different sphingomyelinases. The diversity and cellular topology of ceramide allow it to exert multiple biologies. Furthermore, ceramide can be metabolized to many other bioactive sphingolipids. Ceramide, coming from sphingomyelin or other complex sphingolipids, can be hydrolyzed to sphingosine, which can easily change cellular localization. In turn, sphingosine can be recycled to ceramide and to sphingomyelin in the endoplasmic reticulum, completing the sphingomyelin cycle. Our understanding of the roles of various sphingolipids in the regulation of different cellular processes has come from studying the enzymes that regulate these sphingolipids, and their manipulation. The use of pharmacologic inhibitors has been critical for their study, as well as being promising bullets for disease treatment. Some of these diseases involving the sphingomyelin cycle include cancer, inflammation, atherosclerosis, diabetes and some rare diseases such as Niemann–Pick disease. This review will focus on the enzymes involved in the sphingomyelin cycle, their history, and their involvement in pathophysiological processes. Finally, it will describe in details all the small molecules that are being used to inhibit these enzymes and their use in therapeutics.