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:||Biosynthesis → Fatty Acids and Lipids Biosynthesis → Sphingolipid Biosynthesis|
Expected Taxonomic Range: Eukaryota
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 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 [Wang91a]. The pathway occurs in the endoplasmic reticulum.
Superpathways: sphingolipid biosynthesis (mammals)
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
Wang91a: 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
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
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
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
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
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
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
Kim10i: 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
Lynch93: Lynch DV, Fairfield SR (1993). "Sphingolipid Long-Chain Base Synthesis in Plants (Characterization of Serine Palmitoyltransferase Activity in Squash Fruit Microsomes)." Plant Physiol 103(4);1421-1429. PMID: 12232036
Merrill85: Merrill AH, Nixon DW, Williams RD (1985). "Activities of serine palmitoyltransferase (3-ketosphinganine synthase) in microsomes from different rat tissues." J Lipid Res 26(5);617-22. PMID: 4020300
Miyake95a: Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T (1995). "Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin." Biochem Biophys Res Commun 211(2);396-403. PMID: 7794249
Mizutani04: Mizutani Y, Kihara A, Igarashi Y (2004). "Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation." FEBS Lett 563(1-3);93-7. PMID: 15063729
Morales07: Morales PR, Dillehay DL, Moody SJ, Pallas DC, Pruett S, Allgood JC, Symolon H, Merrill AH (2007). "Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation." Drug Chem Toxicol 30(3);197-216. PMID: 17613006
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