The domain responsible for sphingomyelin synthase (SMS) activity

Yeang, Calvin; Varshney, Shweta; Wang, Renxiao; Zhang, Ya; Ye, Deyong; Jiang, Xian‐Cheng

doi:10.1016/j.bbalip.2008.07.002

Cited by 56 publications

(45 citation statements)

References 21 publications

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“…Because these enzymes use the same reaction chemistry ( 5,11,14,22 ), the specifi city for SM and/or CPE synthesis is most likely defi ned by differences in the geometry of the substrate-binding site. These differences would favor binding of either PC (for SM synthesis), phosphatidylethanolamine (for CPE synthesis), or both.…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase

Ternes

Brouwers

Dikkenberg

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org leafl et of the plasma membrane (PM) where its high packing density and affi nity for cholesterol contributes to the barrier function of the organelle ( 1 ). SM and cholesterol form concentration gradients along the exocytic pathway that are thought to affect protein sorting through hydrophobic matching of membrane spans ( 2, 3 ). Moreover, SM can be hydrolyzed by neutral SMases at the PM to form phosphocholine and the proapoptotic signaling molecule ceramide. This enzymatic reaction is part of an antiproliferative, sphingolipid-mediated signal transduction pathway that controls cell cycle arrest, differentiation, and apoptosis in response to growth factor deprivation, cytokines, ionizing radiation, heat, and chemotherapy ( 4 ). SM synthesis is mediated by a phosphatidylcholine (PC):ceramide cholinephosphotransferase or SM synthase (EC 2.7.8.27). This enzyme catalyzes the transfer of phosphocholine from PC onto ceramide, yielding SM and diacylglycerol ( 5 ). Mammalian cells also produce small amounts of the SM analog ceramide phosphoethanolamine (CPE). However, very little is known about the biological role of this analog or about the enzyme(s) responsible for its production. Two CPE synthase activities have been described in mammalian cells, one enriched in a microsomal fraction [presumably endoplasmic reticulum (ER)] and the other one associated with the PM ( 6-9 ). As PE serves as the headgroup donor for both activities, the enzyme(s) involved can be classifi ed as PE:ceramide Abstract Sphingolipids are vital components of eukaryotic membranes involved in the regulation of cell growth, death, intracellular traffi cking, and the barrier function of the plasma membrane (PM). While sphingomyelin (SM) is the major sphingolipid in mammals, previous studies indicate that mammalian cells also produce the SM analog ceramide phosphoethanolamine (CPE). Little is known about the biological role of CPE or the enzyme(s) responsible for CPE biosynthesis. SM production is mediated by the SM synthases SMS1 in the Golgi and SMS2 at the PM, while a closely related enzyme, SMSr, has an unknown biochemical function. We now demonstrate that SMS family members display striking differences in substrate specifi city, with SMS1 and SMSr being monofunctional enzymes with SM and CPE synthase activity, respectively, and SMS2 acting as a bifunctional enzyme with both SM and CPE synthase activity. In agreement with the PM residency of SMS2, we show that both SM and CPE synthase activities are enhanced at the surface of SMS2-overexpressing HeLa cells. Our fi ndings reveal an unexpected diversity in substrate specifi city among SMS family members that should enable the design of specifi c inhibitors to target the biological role of each enzyme individually.-Ternes, P., J. EMBO Long-Term Fellowship (to P.T.) (to J.C.M.H.). and by grants from the Dutch Organization of Sciences (NWO-CW) and the Utrecht University High Potential Program

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Section: Discussionmentioning

confidence: 99%

Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase

Ternes

Brouwers

Dikkenberg

et al. 2009

Journal of Lipid Research

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“…Further DNase digestion distribution of SMS activity, Sms1 localizes at the Golgi, whereas Sms2 localizes at the Golgi and plasma membrane (14,(16)(17)(18). Modulation of Sms1 or Sms2 activity in most tested cell types has resulted in an alteration of ceramide levels, whereas changes in DAG mass have been elusive (16,(19)(20)(21)(22)(23).…”

Section: Rna Isolation and Reverse Transcription For Real-time Pcrmentioning

confidence: 99%

Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene

Burns

Subathra

Signorelli

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words ceramide • diacylglycerol • imatinib mesylateSphingomyelin synthase (SMS) represents an important class of enzymes responsible for the biosynthesis of SM, a critical structural component of the plasma membrane. While producing SM from ceramide and phosphatidylcholine, SMSs also form diacylglycerol (DAG) (1-7). Therefore, the biological importance of SMSs may reside not only in the biosynthesis of SM but also in the regulation, in opposing directions, of the levels of ceramide, a bioactive molecule that mainly exerts a negative effect on cell proliferation, and DAG, a well-established mitogenic lipid (8).Indeed, increased SMS activity was observed in conditions of enhanced cell proliferation (e.g., regenerating rat liver or stimulation of quiescent astrocytes with basic FGF) (9, 10) and during cell transformation (such as hepatocellular carcinoma vs. normal liver and SV-40-transformed fibroblasts vs. their normal counterpart) (8, 11). Vice versa, inhibition of SMS activity, in a caspase-dependent manner, has been shown to precede the onset of apoptosis induced by either tumor necrosis factor in Kym-1 cells or FAS ligand in Jurkat T cells (12, 13).Two genes have been identifi ed as responsible for SMS activity in mammalian cells, SMS1 and SMS2 (14, 15). The aminoacidic sequence of the proteins encoded by these two genes mainly differs in their N-termini, with Sms1 carrying a sterile ␣ motif absent in Sms2. In agreement with previous biochemical studies assessing the intracellular Abstract Sphingomyelin synthase (SMS) produces sphingomyelin while consuming ceramide (a negative regulator of cell proliferation) and forming diacylglycerol (DAG) (a mitogenic factor). Therefore, enhanced SMS activity could favor cell proliferation. To examine if dysregulated SMS contributes to leukemogenesis, we measured SMS activity in several leukemic cell lines and found that it is highly elevated in K562 chronic myelogenous leukemia (

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“…Fusion of this domain to the N-terminus of SMS2 does not affect the subcellular distribution of SMS2, nor does its removal from SMS1 lead to redistribution of that enzyme. 64 Hence, it appears that the SAM domain is not involved in targeting SMS1 to the Golgi apparatus.…”

Section: Structural Organization and Reaction Chemistry Of Sms Familymentioning

confidence: 99%

“…Consistent with this model, mutation of one of the histidine or aspartate residues that make up the catalytic triad is sufficient to abolish sphingomyelin synthase activity of SMS1 and SMS2 without affecting their subcellular distribution. 64 A remarkable difference between the two SMS isoforms is that SMS1, but not SMS2, contains a N-terminal Sterile Alpha Motif or SAM domain. 58,60 SAM domains have been shown to homoand hetero-oligomerize, forming multiple self-association architectures.…”

Section: Structural Organization and Reaction Chemistry Of Sms Familymentioning

confidence: 99%

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

Holthuis

Luberto

2010

Advances in Experimental Medicine and Biology

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In the last five years tremendous progress has been made toward the understanding of the mechanisms that govern sphingomyelin (SM) synthesis in animal cells. In line with the complexity of most biological processes, also in the case of SM biosynthesis, the more we learn the more enigmatic and finely tuned the system appears. Therefore with this review we aim first, at highlighting the most significant discoveries that advanced our knowledge and understanding of SM biosynthesis, starting from the discovery of SM to the identification of the enzymes responsible for its production; and second, at discussing old and new riddles that such discoveries pose to current investigators.

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The domain responsible for sphingomyelin synthase (SMS) activity

Cited by 56 publications

References 21 publications

Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase

Sphingomyelin synthase SMS2 displays dual activity as ceramide phosphoethanolamine synthase

Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

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