Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Adada, Mohamad M.; Luberto, Chiara; Canals, Daniel

doi:10.1016/j.chemphyslip.2015.07.008

Cited by 104 publications

(83 citation statements)

References 180 publications

(172 reference statements)

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“…SM also serves as receptor for viruses and pore-forming toxins (8,9). Moreover, the plasma membrane pool of SM acts as a reservoir of lipid signaling molecules, the liberation of which is catalyzed by neutral, alkaline, or acidic SMases in response to diverse stimuli (10). Ceramide generated by this pathway, along with its downstream metabolites sphingosine and sphingo sine1phosphate, are critical regulators of cell survival, proliferation, and migration (11).…”

Section: Synthesis Of Clickable Ceramide Analogmentioning

confidence: 99%

Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases

Kol¹,

Panatala²,

Nordmann³

et al. 2016

Journal of Lipid Research

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Section: Synthesis Of Clickable Ceramide Analogmentioning

confidence: 99%

Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases

Kol¹,

Panatala²,

Nordmann³

et al. 2016

Journal of Lipid Research

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“…This includes studies of how altering lipid composition influences biological functions. In this regard, exchange should greatly extend what can be achieved by modifying lipids with inhibitors or engineering modified lipid synthesis pathways (6,7). Exchange may be useful to introduce a very wide variety of lipids, lipids with defined headgroup and single acyl chain composition, and as shown here, unnatural lipids.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the ability to manipulate the lipid composition of living cell membrane would provide a useful tool for use in the research and development of cell membrane-mediated pathological disease. At present, there are limited approaches to exploring lipid function by altering lipid composition, using synthesis inhibitors and metabolic engineering (6)(7)(8). However, inhibitor molecules are slow acting, limited to certain classes of lipids, and not always sufficiently specific.…”

mentioning

confidence: 99%

Efficient replacement of plasma membrane outer leaflet phospholipids and sphingolipids in cells with exogenous lipids

Kim

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

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Our understanding of membranes and membrane lipid function has lagged far behind that of nucleic acids and proteins, largely because it is difficult to manipulate cellular membrane lipid composition. To help solve this problem, we show that methyl-α-cyclodextrin (MαCD)-catalyzed lipid exchange can be used to maximally replace the sphingolipids and phospholipids in the outer leaflet of the plasma membrane of living mammalian cells with exogenous lipids, including unnatural lipids. In addition, lipid exchange experiments revealed that 70-80% of cell sphingomyelin resided in the plasma membrane outer leaflet; the asymmetry of metabolically active cells was similar to that previously defined for erythrocytes, as judged by outer leaflet lipid composition; and plasma membrane outer leaflet phosphatidylcholine had a significantly lower level of unsaturation than phosphatidylcholine in the remainder of the cell. The data also provided a rough estimate for the total cellular lipids residing in the plasma membrane (about half). In addition to such lipidomics applications, the exchange method should have wide potential for investigations of lipid function and modification of cellular behavior by modification of lipids.lipid exchange | plasma membrane outer leaflet | lipid asymmetry | methyl-alpha-cyclodextrin | mass spectrometry

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“…Ceramide molecules act as hubs in the sphingolipid pathway as they are readily converted by sphingomyelinases (SMases), ceramidases, ceramide kinase, or glucosyltransferases, thereby maintaining ceramide levels under homeostatic conditions (1,2). In response to cellular stress or ligation of specific receptors, it is predominantly because of activation of SMases that ceramides condense into microdomains, thereby locally altering the biophysical properties of cellular membranes (3)(4)(5)(6).…”

mentioning

confidence: 99%

A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

Collenburg

Walter

Burgert

et al. 2016

The Journal of Immunology

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Sphingolipids are major components of the plasma membrane. In particular, ceramide serves as an essential building hub for complex sphingolipids, but also as an organizer of membrane domains segregating receptors and signalosomes. Sphingomyelin breakdown as a result of sphingomyelinase activation after ligation of a variety of receptors is the predominant source of ceramides released at the plasma membrane. This especially applies to T lymphocytes where formation of ceramide-enriched membrane microdomains modulates TCR signaling. Because ceramide release and redistribution occur very rapidly in response to receptor ligation, novel tools to further study these processes in living T cells are urgently needed. To meet this demand, we synthesized nontoxic, azido-functionalized ceramides allowing for bio-orthogonal click-reactions to fluorescently label incorporated ceramides, and thus investigate formation of ceramide-enriched domains. Azido-functionalized C6-ceramides were incorporated into and localized within plasma membrane microdomains and proximal vesicles in T cells. They segregated into clusters after TCR, and especially CD28 ligation, indicating efficient sorting into plasma membrane domains associated with T cell activation; this was abolished upon sphingomyelinase inhibition. Importantly, T cell activation was not abrogated upon incorporation of the compound, which was efficiently excluded from the immune synapse center as has previously been seen in Ab-based studies using fixed cells. Therefore, the functionalized ceramides are novel, highly potent tools to study the subcellular redistribution of ceramides in the course of T cell activation. Moreover, they will certainly also be generally applicable to studies addressing rapid stimulation-mediated ceramide release in living cells.

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Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Cited by 104 publications

References 180 publications

Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases

Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases

Efficient replacement of plasma membrane outer leaflet phospholipids and sphingolipids in cells with exogenous lipids

A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells

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