Characterization of Ceramide Synthase 2

Ceramide is an important lipid signaling molecule and a key intermediate in sphingolipid biosynthesis. Recent studies have implied a previously unappreciated role for the ceramide N-acyl chain length, inasmuch as ceramides containing specific fatty acids appear to play defined roles in cell physiology. The discovery of a family of mammalian ceramide synthases (CerS), each of which utilizes a restricted subset of acyl-CoAs for ceramide synthesis, strengthens this notion. We now report the characterization of mammalian CerS2. qPCR analysis reveals that CerS2 mRNA is found at the highest level of all CerS and has the broadest tissue distribution. CerS2 has a remarkable acyl-CoA specificity, showing no activity using C16:0-CoA and very low activity using C18:0, rather utilizing longer acyl-chain CoAs (C20–C26) for ceramide synthesis. There is a good correlation between CerS2 mRNA levels and levels of ceramide and sphingomyelin containing long acyl chains, at least in tissues where CerS2 mRNA is expressed at high levels. Interestingly, the activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (S1P), via interaction of S1P with two residues that are part of an S1P receptor-like motif found only in CerS2. These findings provide insight into the biochemical basis for the ceramide N-acyl chain composition of cells, and also reveal a novel and potentially important interplay between two bioactive sphingolipids that could be relevant to the regulation of sphingolipid metabolism and the opposing functions that these lipids play in signaling pathways. Ceramide is an important lipid signaling molecule and a key intermediate in sphingolipid biosynthesis. Recent studies have implied a previously unappreciated role for the ceramide N-acyl chain length, inasmuch as ceramides containing specific fatty acids appear to play defined roles in cell physiology. The discovery of a family of mammalian ceramide synthases (CerS), each of which utilizes a restricted subset of acyl-CoAs for ceramide synthesis, strengthens this notion. We now report the characterization of mammalian CerS2. qPCR analysis reveals that CerS2 mRNA is found at the highest level of all CerS and has the broadest tissue distribution. CerS2 has a remarkable acyl-CoA specificity, showing no activity using C16:0-CoA and very low activity using C18:0, rather utilizing longer acyl-chain CoAs (C20–C26) for ceramide synthesis. There is a good correlation between CerS2 mRNA levels and levels of ceramide and sphingomyelin containing long acyl chains, at least in tissues where CerS2 mRNA is expressed at high levels. Interestingly, the activity of CerS2 can be regulated by another bioactive sphingolipid, sphingosine 1-phosphate (S1P), via interaction of S1P with two residues that are part of an S1P receptor-like motif found only in CerS2. These findings provide insight into the biochemical basis for the ceramide N-acyl chain composition of cells, and also reveal a novel and potentially important interplay between two bioactive sphingolipids that could be relevant to the regulation of sphingolipid metabolism and the opposing functions that these lipids play in signaling pathways. The past decade has seen an upsurge of interest in sphingolipids (SLs), 2The abbreviations used are:SLsphingolipidCerSceramide synthaseESI-MS/MSelectrospray ionization-tandem mass spectrometryHexCerhexosylceramideSKsphingosine kinaseS1Psphingosine 1-phosphateLCliquid chromatographyHAhemagglutininqPCRquantitative PCRsiRNAsmall interference RNACMVcytomegalovirusSMsphingomyelin. due largely to the extraordinary number of complex species that have been found in eukaryotes (1Merrill Jr., A.H. Wang M.D. Park M. Sullards M.C. Trends Biochem. Sci. 2007; 32: 457-468Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), as well as the involvement of the lipid backbones in signaling pathways as both first and second messengers (2Lahiri S. Futerman A.H. Cell Mol. Life Sci. 2007; 64: 2270-2284Crossref PubMed Scopus (273) Google Scholar, 3Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar, 4Futerman A.H. Hannun Y.A. EMBO Reps. 2004; 5: 777-782Crossref PubMed Scopus (549) Google Scholar). Indeed, ceramide (3Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (771) Google Scholar) and sphingosine 1-phosphate (S1P) (5Spiegel S. Milstien S. Nat. Rev. Mol. Cell. Biol. 2003; 4: 397-407Crossref PubMed Scopus (1791) Google Scholar) appear to play opposing roles in cell proliferation, migration, and survival, which underscores how the balance of the levels of these two lipids has ramifications for diverse pathological and pathophysiological processes (6Hait N.C. Oskeritzian C.A. Paugh S.W. Milstien S. Spiegel S. Biochim. Biophys. Acta. 2006; 1758: 2016-2026Crossref PubMed Scopus (419) Google Scholar, 7Schenck M. Carpinteiro A. Grassme H. Lang F. Gulbins E. Arch. Biochem. Biophys. 2007; 462: 171-175Crossref PubMed Scopus (78) Google Scholar, 8Ogretmen B. Hannun Y.A. Nat. Rev. Cancer. 2004; 4: 604-616Crossref PubMed Scopus (1032) Google Scholar). sphingolipid ceramide synthase electrospray ionization-tandem mass spectrometry hexosylceramide sphingosine kinase sphingosine 1-phosphate liquid chromatography hemagglutinin quantitative PCR small interference RNA cytomegalovirus sphingomyelin. In mammals, ceramide is synthesized by a family of six enzymes, ceramide synthases (CerS) 1–6 (9Pewzner-Jung Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar), each of which uses a relatively restricted subset of fatty acyl-CoAs for N-acylation (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 12Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2005; 390: 263-271Crossref PubMed Scopus (321) Google Scholar) of the sphingoid long chain base. Thus, CerS1 and CerS5, which are the best characterized CerS proteins, synthesize C18- and C16-ceramide, respectively (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 13Koybasi S. Senkal C.E. Sundararaj K. Spassieva S. Bielawski J. Osta W. Day T.A. Jiang J.C. Jazwinski S.M. Hannun Y.A. Obeid L.M. Ogretmen B. J. Biol. Chem. 2004; 279: 44311-44319Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 14Lahiri S. Futerman A.H. J. Biol. Chem. 2005; 280: 33735-33738Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), whereas CerS2 and -3 appear to have a broader specificity (15Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar). The existence of these six CerS genes in mammals implies an important and largely unexplored role for ceramides containing specific fatty acids in cell physiology (9Pewzner-Jung Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar). One possibility is that different tissues contain ceramides with defined fatty acids, necessitating the presence of specific CerS in specific tissues for their synthesis. However, with the exception of an early study by semi-quantitative reverse transcription-PCR (11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), little is known about CerS tissue distribution. This study describes the characterization of CerS2, which has received relatively little attention. We demonstrate that CerS2 mRNA occurs at much higher levels than most other CerS, has the broadest tissue distribution, and synthesizes ceramides containing mainly C20–C26 fatty acids, with little or no synthesis of C16- and C18-ceramides. Moreover, CerS2 activity is inhibited by S1P via interaction of S1P with an S1P receptor-like motif found only in CerS2. This unique link between S1P and a key enzyme of ceramide metabolism might be of significance to understanding the interplay between these two lipids in metabolic and in signaling pathways. Materials—d-erythro-[4,5-3H]Sphinganine was synthesized as described (16Hirschberg K. Rodger J. Futerman A.H. Biochem. J. 1993; 290: 751-757Crossref PubMed Scopus (165) Google Scholar). S1P was from Sigma-Aldrich or from Avanti Polar Lipids (Alabaster, AL); fatty acyl-CoAs and the internal standards for liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI MS/MS) were also from Avanti. An anti-protein disulfide isomerase antibody was from Stressgen (Victoria, BC, Canada), and an anti-hemagglutinin (HA) antibody was from Santa Cruz Biotechnology (Santa Cruz, CA). Horseradish peroxidase was from Jackson Laboratories (Bar Harbor, MA). Pfu polymerase was from Promega (Madison, WI) or from Stratagene (La Jolla, CA). TaqMan™ was from Applied Biosystems (Foster City, CA). A PerfectPure RNA Kit was from 5Prime (Gaithersburg, MD). A Reverse-iT first strand synthesis kit was from Thermo Scientific (Epsom, UK). Silica gel 60 TLC plates were from Merck. All solvents were of analytical grade and were purchased from Biolab (Jerusalem, Israel). Real-time qPCR—Tissues were harvested from 6- to 8-week-old mice; females were used for all tissues except prostate and testis. RNA was isolated using a PerfectPure RNA kit according to manufacturer's instructions, which included a DNase step. cDNA synthesis was performed using a Reverse-iT first strand synthesis kit using random decamers with 30-min incubation at 42 °C and then at 47 °C. cDNA generation demonstrated equivalent efficiency of synthesis with input RNA ranging from 15 to 500 of RNA was used to levels of CerS using TaqMan™ analysis and a CerS levels were in all tissues as with quantitative analysis was in by to a via of for each for of RNA all PCR were to the of for CerS1 CerS2 and and for were from Applied was from Applied Biosystems and to and used for generation of qPCR are in used in the used for generation of qPCR were used to for of the qPCR used to CerS2 and for of A and were used for of the of the and and for the A and were used for of the of the and and for the In the second the two were using an PCR step. of °C were used for the first and a of °C for the CerS2 CerS2 used for mRNA analysis were used to for of the qPCR A and were used for of the of the and and for the A and were used for of the of the and and for the In the second the two were using an PCR step. of °C were used for the first and a of °C for the in a RNA were into the according to the manufacturer's were for and The were all known CerS2 (9Pewzner-Jung Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar) and other CerS CerS2 was by with the using the of RNA was using the Kit was performed using the strand cDNA synthesis kit and PCR was performed using the in Cell and were in with and were with CerS genes using the of of which CerS genes S. H. J. A. Futerman A.H. 2007; PubMed Scopus Google Scholar) in a with an were from CerS2 was into a containing an which was at the of was performed using PCR and by were using a mass and an mass as described previously (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, M.C. Merrill Jr., A.H. Scholar, Jr., A.H. Sullards M.C. Allegood J.C. S. Wang E. 2005; PubMed Scopus Google Scholar). were with CerS2, or and harvested by by with and The were with an internal Polar then and by (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, M.C. Merrill Jr., A.H. Scholar, Jr., A.H. Sullards M.C. Allegood J.C. S. Wang E. 2005; PubMed Scopus Google Scholar). tissue the tissues were from at of as described and were to of tissue were with the internal and by ESI CerS activity was as described previously (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 14Lahiri S. Futerman A.H. J. Biol. Chem. 2005; 280: 33735-33738Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) using cell and of fatty acyl-CoA for at °C S. H. J. A. Futerman A.H. 2007; PubMed Scopus Google Scholar). of were used for from with different CerS in that the of the was with to S. H. J. A. Futerman A.H. 2007; PubMed Scopus Google Scholar), and different acyl-CoAs were used in with the specificity of each CerS (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 12Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2005; 390: 263-271Crossref PubMed Scopus (321) Google Scholar, 14Lahiri S. Futerman A.H. J. Biol. Chem. 2005; 280: 33735-33738Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar) of CerS2, of of of and of in was to the to of of was performed by as described for and (11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), using as a and disulfide isomerase as an CerS in early study the tissue of CerS mRNA by semi-quantitative reverse transcription-PCR that each CerS has a unique tissue distribution, with CerS2 mRNA the most expressed (11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). We have now for quantitative PCR in which the are to of and are these CerS mRNA levels in In with the study (11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), CerS2 is However, due to the and of now demonstrate that CerS2 mRNA levels are higher than of the other CerS in as much as an of higher CerS2 of was in and with levels of in most other In CerS1 and -3 were expressed mainly in and and in and (15Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar), and were in other was expressed at the highest levels in and in the other was expressed at levels of of RNA and were expressed in most with levels of of RNA CerS2 to be low in tissues highest levels of CerS1 or and of the specificity of CerS2 CerS2 is most to (9Pewzner-Jung Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar), which was to synthesize ceramides containing mainly and fatty acids (15Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar). in that CerS2 uses a of ceramides containing and fatty acids synthesize ceramides containing fatty acids and synthesizes only and levels of In analysis of CerS2 activity using a of acyl-CoAs was with the acyl-CoA specificity of CerS2, were with two different in a and with with the CerS2 mRNA levels were with and with CerS using as a of activity with with of levels of ceramides by with was with of CerS2 Thus, CerS2 has a different of of acyl-CoAs than the other CerS, using mainly to is to synthesize and to other CerS for which the has been by (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), rather than by biochemical of J. H. A. Bielawski J. Obeid L.M. J. Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), CerS2 is to the with no with a A.H. Biochim. Biophys. Acta. 2006; 1758: PubMed Scopus Google Scholar). between CerS mRNA and Ceramide CerS2 mRNA is and found at high levels in tissues is known about how this is to levels of of the CerS2 or of the of ceramides containing acids, the synthesized by CerS2 and are no to CerS2, antibody is for CerS2 no to CerS2. the ceramide by to tissues that high levels of CerS2 mRNA are in the ceramide in sphingomyelin and of the ceramide N-acyl chain with that of the levels of of CerS mRNA reveals that the two tissues with highest CerS2 mRNA and also have the highest of to also has high of acyl in and as the N-acyl chain composition of from that of ceramides and the other tissues and CerS2 is than the of the other CerS, and the of and and are Interestingly, for two of these tissues and high of that are other than the of the CerS mRNA that the distribution, in complex and of CerS2 by number of studies have that S1P ceramide synthesis, and this interaction be of the by which S1P M. H. N.C. H. H. C. M. Merrill Jr., A.H. Milstien S. Spiegel S. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. S. C. A. J. Spiegel S. Sci. S. A. PubMed Scopus Google Scholar, Bielawski J. C. Obeid L.M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google is no showing of ceramide synthesis by We S1P can the activity of CerS in at to no ceramide synthesis by and inhibited CerS2 activity by a of and The that S1P was to the of CerS2 rather at a analysis are to the most of for all CerS the of the found that a of CerS2 has to two of of the S1P Biochem. J. PubMed Scopus Google Scholar). The of the two was to S1P was by analysis in other CerS these two residues were as for S1P to the Wang K. Spiegel S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), to residues and in CerS2 these residues are found in other CerS, were by the as part of an S1P of each of these residues no S1P of CerS2 of both residues to the of S1P CerS2 the activity of CerS2 Thus, S1P can CerS2 activity via a interaction with an S1P receptor-like motif found in CerS2 via an S1P receptor-like residues that are part of the S1P in CerS2 are residues are activity of CerS2 and CerS2 a which was with analysis also that was no in levels. of S1P CerS2 activity and activity of are for performed in and are expressed as of the of CerS1 (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar) as a ceramide has been in the six of this mammalian studies to have the acyl-CoA specificity of the (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 12Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2005; 390: 263-271Crossref PubMed Scopus (321) Google Scholar, Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar). However, with the exception of in ceramide synthase in Y. Kihara A. Igarashi Y. Biochem. J. 2005; 390: 263-271Crossref PubMed Scopus (321) Google Scholar), CerS2 has been well We now this and report the that CerS2 mRNA is that CerS2 a remarkable fatty acyl-CoA specificity, showing no activity with very low or no activity with and little longer chain fatty and that CerS2 can be regulated by these important in both the of CerS, and in their biochemical of The of CerS2 from other CerS can also be from study of CerS2 has a a low number of and with a of containing and and a low of CerS2 is that are early the cell of These are of a analysis performed using E. Trends 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. 2005; PubMed Scopus Google Scholar, M. B. S. S. Y. 2007; 390: PubMed Scopus Google Scholar) the possibility that the CerS2 is a Interestingly, no other CerS genes these has of a and of were by of each using the The presence or of and were in and using the that for and low in the were using the which for of or longer with is and the all The is and the all in a a is defined as a with levels of from tissue to tissue and that a that is in However, the of qPCR and analysis has that genes can in levels in tissues and can to Y. M. J. 2007; PubMed Scopus Google Scholar, S. M. J. S. J. Biochem. Mol. Biol. 2007; PubMed Google Scholar). The that CerS2 of the of a that is a ceramide However, of the signaling functions of ceramides have been to in Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar), CerS2 The tissue of CerS2 might that ceramides synthesized by CerS2 are in metabolism in most cells, whereas other CerS, which are found at levels and which synthesize a restricted subset of ceramide acyl CerS5, which synthesizes (11Riebeling C. Allegood J.C. Wang E. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2003; 278: 43452-43459Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar), and which synthesizes (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google be in ceramide synthesis in specific tissues specific or as in or cell S. Senkal C.E. Sundararaj K. Spassieva S. Bielawski J. Osta W. Day T.A. Jiang J.C. Jazwinski S.M. Hannun Y.A. Obeid L.M. Ogretmen B. J. Biol. Chem. 2004; 279: 44311-44319Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, Y. H. Bielawski J. Hannun Y.A. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). In this the regulation of CerS2 by via the S1P receptor-like motif in this to the interest the of each CerS, CerS2. In this of in to a in ceramide levels Y. H. Bielawski J. Hannun Y.A. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google the of CerS genes is known in cells, is to from these that S1P levels CerS2 However, of in cells, by and of a was seen in levels of ceramides containing all fatty acids synthesized by CerS2 also and M. H. N.C. H. H. C. M. Merrill Jr., A.H. Milstien S. Spiegel S. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar). CerS2 is found at high levels in cells, and A. H. which be for the in the for the in C16- and levels is be due to regulation of other CerS CerS1 and by Indeed, that are to CerS activity and and to levels of ceramides containing specific acyl Thus, is a relatively good correlation between CerS2 mRNA and levels of and in is a remarkable between the acyl chain composition of and in both tissues contain high levels and high levels of CerS2 levels of C16-ceramide, and are high in of mRNA is highest in this synthesizes mainly long chain also (15Mizutani Y. Kihara A. Igarashi Y. Biochem. J. 2006; 398: 531-538Crossref PubMed Scopus (150) Google Scholar). and levels are high in and which high levels of CerS1 mRNA A. M. Cell Biol. 2007; Scholar), mainly longer acyl chain ceramides in these This levels of regulation of ceramide which most also the of the fatty a in ceramide from the for synthesis in the K. K. S. Y. M. M. M. 2003; PubMed Scopus Google Scholar), has a defined specificity different acyl chain ceramides K. S. K. M. S. K. J. Biol. Chem. 2005; 280: Full Text Full Text PDF Scopus Google and as the to which ceramide in at the where have been found J. W. W. Bielawski J. Obeid L.M. C. J. 2006; PubMed Scopus Google Scholar). is also that is of into specific ceramides and in to findings with CerS1 (10Venkataraman K. Riebeling C. Bodennec J. Riezman H. Allegood J.C. Sullards M.C. Merrill Jr., A.H. Futerman A.H. J. Biol. Chem. 2002; 277: 35642-35649Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar), in which was into with and In and and biochemical between the CerS genes and proteins, and a unique role for CerS2. The that CerS2 activity can be regulated by S1P the for a of biochemical studies to to the between these two important lipid signaling We for the of CerS and Ben-Dor for with with

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