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MetaCyc Pathway: ceramide de novo biosynthesis
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: ceramide de novo biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisSphingolipid Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus

Expected Taxonomic Range: Eukaryota

General Background

Ceramides belong to a diverse class of lipids called sphingolipids that have important biological properties and control many aspects of cellular metabolism [Mullen12]. They are composed of sphingosine linked to a fatty acid via an amide bond. Ceramides make up a large percentage of the cell membrane and are the major lipid constituent of lamellar sheets in the intercellular spaces of the stratum corneum [Coderch03]. These lamellar sheets provide the barrier property of the epidermis.

Besides having structural properties, ceramides can act as a second messengers in the sphingomyelin cycle [Hannun94], and also play a role in cell aging, apoptosis and differentiation [Hannun00]. There are three major pathways for ceramide generation. This pathway describes de novo biosynthesis.

About this Pathway

The defining step in the de novo biosynthesis of ceramides is the pyridoxal-5'-phosphate-dependent condensation of palmitoyl-CoA with L-serine catalyzed by serine palmitoyltransferase [Weiss97]. The resultant 3-dehydrosphinganine is immediately reduced to D-erythro-sphinganine in an NADPH dependent reaction catalyzed by 3-ketodihydrosphingosine reductase. Dihydroceramide synthase catalyzes the acylation of sphinganine to yield a dihydroceramide, followed by a desaturation at the 4,5 position to form a ceramide [Michel97].

The last two steps of the pathway were decided by the discovery of the fungal secondary metabolite fumonisin B1 [Merrill96]. Fumonisin B1 is a potent inhibitor of the N-acylation of sphingoid bases and blocks the pathway at the dihydroceramide synthase step. This clarified that the latter part of the pathway proceeds first by acylation and then desaturation instead of vice versa [Wang91b]. The pathway occurs in the endoplasmic reticulum.

Superpathways: sphingolipid biosynthesis (mammals)

Variants: ceramide phosphoethanolamine biosynthesis, sphingolipid biosynthesis (plants), sphingolipid biosynthesis (yeast)

Created 31-Jul-2008 by Evsikov A, The Jackson Laboratory
Revised 21-Mar-2013 by Weerasinghe D, SRI International


Coderch03: Coderch L, Lopez O, de la Maza A, Parra JL (2003). "Ceramides and skin function." Am J Clin Dermatol 4(2);107-29. PMID: 12553851

Cuvillier02: Cuvillier O (2002). "Sphingosine in apoptosis signaling." Biochim Biophys Acta 1585(2-3);153-62. PMID: 12531549

Hannun00: Hannun YA, Luberto C (2000). "Ceramide in the eukaryotic stress response." Trends Cell Biol 10(2);73-80. PMID: 10652518

Hannun94: Hannun YA (1994). "The sphingomyelin cycle and the second messenger function of ceramide." J Biol Chem 269(5);3125-8. PMID: 8106344

Merrill96: Merrill AH, Wang E, Vales TR, Smith ER, Schroeder JJ, Menaldino DS, Alexander C, Crane HM, Xia J, Liotta DC, Meredith FI, Riley RT (1996). "Fumonisin toxicity and sphingolipid biosynthesis." Adv Exp Med Biol 392;297-306. PMID: 8850625

Michel97: Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH (1997). "Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide." J Biol Chem 272(36);22432-7. PMID: 9312549

Mullen12: Mullen TD, Hannun YA, Obeid LM (2012). "Ceramide synthases at the centre of sphingolipid metabolism and biology." Biochem J 441(3);789-802. PMID: 22248339

Wang91b: Wang E, Norred WP, Bacon CW, Riley RT, Merrill AH (1991). "Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme." J Biol Chem 266(22);14486-90. PMID: 1860857

Weiss97: Weiss B, Stoffel W (1997). "Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis." Eur J Biochem 249(1);239-47. PMID: 9363775

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Basu98: Basu J, Li Z (1998). "The Des-1 protein, required for central spindle assembly and cytokinesis, is associated with mitochondria along the meiotic spindle apparatus and with the contractile ring during male meiosis in Drosophila melanogaster." Mol Gen Genet 259(6);664-73. PMID: 9819060

Beeler98: Beeler T, Bacikova D, Gable K, Hopkins L, Johnson C, Slife H, Dunn T (1998). "The Saccharomyces cerevisiae TSC10/YBR265w gene encoding 3-ketosphinganine reductase is identified in a screen for temperature-sensitive suppressors of the Ca2+-sensitive csg2Delta mutant." J Biol Chem 273(46);30688-94. PMID: 9804843

Cadena97: Cadena DL, Kurten RC, Gill GN (1997). "The product of the MLD gene is a member of the membrane fatty acid desaturase family: overexpression of MLD inhibits EGF receptor biosynthesis." Biochemistry 36(23);6960-7. PMID: 9188692

Causeret00: Causeret C, Geeraert L, Van der Hoeven G, Mannaerts GP, Van Veldhoven PP (2000). "Further characterization of rat dihydroceramide desaturase: tissue distribution, subcellular localization, and substrate specificity." Lipids 35(10);1117-25. PMID: 11104018

Chao11: Chao DY, Gable K, Chen M, Baxter I, Dietrich CR, Cahoon EB, Guerinot ML, Lahner B, Lu S, Markham JE, Morrissey J, Han G, Gupta SD, Harmon JM, Jaworski JG, Dunn TM, Salt DE (2011). "Sphingolipids in the root play an important role in regulating the leaf ionome in Arabidopsis thaliana." Plant Cell 23(3);1061-81. PMID: 21421810

Endo96: Endo K, Akiyama T, Kobayashi S, Okada M (1996). "Degenerative spermatocyte, a novel gene encoding a transmembrane protein required for the initiation of meiosis in Drosophila spermatogenesis." Mol Gen Genet 253(1-2);157-65. PMID: 9003299

Gable00: Gable K, Slife H, Bacikova D, Monaghan E, Dunn TM (2000). "Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity." J Biol Chem 275(11);7597-603. PMID: 10713067

Gable02: Gable K, Han G, Monaghan E, Bacikova D, Natarajan M, Williams R, Dunn TM (2002). "Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase." J Biol Chem 277(12);10194-200. PMID: 11781309

Geeraert97: Geeraert L, Mannaerts GP, van Veldhoven PP (1997). "Conversion of dihydroceramide into ceramide: involvement of a desaturase." Biochem J 327 ( Pt 1);125-32. PMID: 9355743

Han09: Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH, Harmon JM, Dunn TM (2009). "Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities." Proc Natl Acad Sci U S A 106(20);8186-91. PMID: 19416851

Hanada03: Hanada K (2003). "Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism." Biochim Biophys Acta 1632(1-3);16-30. PMID: 12782147

Hojjati05: Hojjati MR, Li Z, Jiang XC (2005). "Serine palmitoyl-CoA transferase (SPT) deficiency and sphingolipid levels in mice." Biochim Biophys Acta 1737(1);44-51. PMID: 16216550

Hornemann06: Hornemann T, Richard S, Rutti MF, Wei Y, von Eckardstein A (2006). "Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase." J Biol Chem 281(49);37275-81. PMID: 17023427

Jiang98c: Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM (1998). "Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human." Genome Res 8(12);1259-72. PMID: 9872981

Kihara04: Kihara A, Igarashi Y (2004). "FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane." J Biol Chem 279(47);49243-50. PMID: 15328338

Kim10e: Kim SK, Noh YH, Koo JR, Yun HS (2010). "Effect of expression of genes in the sphingolipid synthesis pathway on the biosynthesis of ceramide in Saccharomyces cerevisiae." J Microbiol Biotechnol 20(2);356-62. PMID: 20208441

Kim12: Kim HJ, Qiao Q, Toop HD, Morris JC, Don AS (2012). "A fluorescent assay for ceramide synthase activity." J Lipid Res 53(8);1701-7. PMID: 22661289

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lederer94: Lederer F (1994). "The cytochrome b5-fold: an adaptable module." Biochimie 76(7);674-92. PMID: 7893819

Lubert: Lubert Stryer "Biochemistry." ISBN 0-7167-1226-1.

Showing only 20 references. To show more, press the button "Show all references".

Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by Pathway Tools version 19.5 (software by SRI International) on Mon May 2, 2016, biocyc14.