Ceramide synthase 5

Ceramide synthase 5
Identifiers
Symbol CerS5
Alt. symbols LASS5
Entrez 91012
HUGO 23749
OMIM 615335
PDB 2CQX
RefSeq NM_147190
UniProt Q8N5B7
Other data
EC number 2.3.1.24
Locus Chr. 12 q13.12

Ceramide synthase 5 (CerS5) is the enzyme encoded in humans by the CERS5 gene.

Function

CerS5 robustly synthesizes C16-ceramide,[1] which is often considered to be an important pro-apoptotic ceramide.[2] De novo ceramide synthesis is an essential trigger for Bax activation in hypoxia/reoxygenation. Following hypoxia/reoxygenation, CerS5 expression is elevated. Upon knocking down acid sphingomyelinase and CerS5 in NTERA-2 cells, Bax localization to mitochondria was reduced, indicating the importance of CerS5 activity in the apoptosis pathway.[3]

Tissue distribution

CerS5 (TRH4) mRNA is found in all tissues and is strongly expressed in muscle and brain.[4] CerS5 is the major ceramide synthase detected in lung epithelia. Knock-down research in respiratory epithelium using CerS5 siRNA or fumonisin B1 reduced total CerS activity by 45% or 78%, respectively,[5] indicating that CerS5 indeed contributes significantly to ceramide synthesis in lung. In the brain, CerS5 mRNA is detected in most cells within the gray and white matter tissues.[6]

Clinical significance

CerS5 sensitizes cells to the chemotherapeutic drugs doxorubicin and vincristine, but not to cisplatin or carboplatin.[7]

A splice variant of CerS5 is expressed in lymphoma and other tumor cells and contribute to tumor recognition by the immune system.[8] In response to upregulation of tumor suppressor protein p53, C16-ceramide levels were increased in leukemia and colon cancer cells, as were levels of CerS5 mRNA in the leukemia cells, but not in the colon cancer cells. For this reason, CerS5 looks like a promising target for the regulation of cancer and of cell death pathways.[9]

References

  1. ↑ Sujoy Lahiri, Anthony H Futerman (2005). "LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor.". J Biol Chem 280 (40): 33735–8. doi:10.1074/jbc.m506485200.
  2. ↑ Levy M, Futerman AH (2010). "Mammalian ceramide synthases.". IUBMB Life 62 (5): 347–56. doi:10.1002/iub.319. PMC 2858252. PMID 20222015.
  3. ↑ Jin J, Hou Q, Mullen TD, Zeidan YH, Bielawski J, Kraveka JM, et al. (2008). "Ceramide generated by sphingomyelin hydrolysis and the salvage pathway is involved in hypoxia/reoxygenation-induced Bax redistribution to mitochondria in NT-2 cells.". J Biol Chem 283 (39): 26509–17. doi:10.1074/jbc.M801597200. PMC 2546549. PMID 18676372.
  4. ↑ Riebeling C, Allegood JC, Wang E, Merrill AH Jr, Futerman AH (Oct 2003). "Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors". J Biol Chem 278 (44): 43452–9. doi:10.1074/jbc.M307104200. PMID 12912983.
  5. ↑ Xu Z, Zhou J, McCoy DM, Mallampalli RK (2005). "LASS5 is the predominant ceramide synthase isoform involved in de novo sphingolipid synthesis in lung epithelia.". J Lipid Res 46 (6): 1229–38. doi:10.1194/jlr.M500001-JLR200. PMID 15772421.
  6. ↑ Becker I, Wang-Eckhardt L, Yaghootfam A, Gieselmann V, Eckhardt M (2008). "Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2.". Histochem Cell Biol 129 (2): 233–41. doi:10.1007/s00418-007-0344-0. PMID 17901973.
  7. ↑ Min J, Mesika A, Sivaguru M, Van Veldhoven PP, Alexander H, Futerman AH, et al. (2007). "(Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1.". Mol Cancer Res 5 (8): 801–12. doi:10.1158/1541-7786.MCR-07-0100. PMID 17699106.
  8. ↑ van Hall T, Wolpert EZ, van Veelen P, Laban S, van der Veer M, Roseboom M, et al. (2006). "Selective cytotoxic T-lymphocyte targeting of tumor immune escape variants.". Nat Med 12 (4): 417–24. doi:10.1038/nm1381. PMID 16550190.
  9. ↑ Panjarian S, Kozhaya L, Arayssi S, Yehia M, Bielawski J, Bielawska A, et al. (2008). "De novo N-palmitoylsphingosine synthesis is the major biochemical mechanism of ceramide accumulation following p53 up-regulation.". Prostaglandins Other Lipid Mediat 86 (1-4): 41–8. doi:10.1016/j.prostaglandins.2008.02.004. PMID 18400537.
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