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MetaCyc Pathway: sphingolipid biosynthesis (yeast)
Traceable author statement to experimental support

Pathway diagram: sphingolipid biosynthesis (yeast)

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 : Saccharomyces cerevisiae

Expected Taxonomic Range: Fungi

General Background

Sphingolipids are a class of lipids derived from the unsaturated aliphatic amino alcohol sphingosine that are essential components of the plasma membrane in all eukaryotic cells. Sphingolipids concentrate with sterols ( cholesterol in animals and ergosterol in yeast) to form lipid rafts, specialized membrane microdomains implicated in a variety of cellular processes, including sorting of membrane proteins and lipids, as well as organizing and regulating signaling cascades [Bagnat02].

The sphingosine backbone of sphingolipids (often referred to as the sphingoid base) is amide-linked to an acyl group, such as a fatty acid, and is often also O-linked to a head group. In yeast the head group is inositol, which in some cases is modified further by the addition of a mannose sugar and a second inositol.

The sphingoid bases often consists of modified forms of sphingosine. When the double bond at position 4 is saturated, it is named D-erythro-sphinganine. In yeast the sphingoid base is a C4-hydroxylated sphinganine, known as phytosphingosine, and the ceramides that it forms are known as phytoceramides.

About This Pathway

De novo sphingolipid biosynthesis is required for survival, and loss of the pathway affects growth and viability. Even though mammals and Saccharomyces cerevisiae produce structurally and chemically different types of sphingoid bases, ceramides, and complex sphingolipids, the early steps in their sphingolipid synthesis pathways, up to formation of ceramides, are similar. The earlier part of the pathway, up to ceramide formation, occurs in the endoplasmic reticulum (ER).

Saccharomyces cerevisiae cells make three complex sphingolipids: inositol-phosphoceramide (IPC), mannose-inositol-phosphoceramide (MIPC), and mannosyl-diinositol-phosphorylceramide [MIP2C] [Dickson02]. The latter makes about 75% of the total sphingolipid content, while the other 25% are divided evenly among the other two [Funato02]. The complex sphingolipids are made in the Golgi apparatus, and this part of the pathway does not have a mammalian counterpart.

It should be noted that the complex sphingolipids are not the only sphingolipids that have biological activity. Several intermediates in sphingolipid biosynthesis have been shown to play important roles on their own as signaling molecules and growth regulators. Both the sphingoid base D-erythro-sphinganine and the phytoceramides have been implicated as secondary messengers in signaling pathways that regulate heat stress response [Jenkins97, FergusonYankey02].

In addition, externally-provided sphingoid bases are phosphorylated by dedicated enzymes, forming sphinganine 1-phosphate and phytosphingosine 1-phosphate, both of which have been shown to be components of a tightly-controlled system that regulates cell growth [Kobayashi03]. The phosphates can be dephosphorylated back to sphingoid bases (see sphingolipid recycling and degradation (yeast)), which then enter the de novo biosynthetic pathway.

Since phosphoinositol-containing sphingolipids are not found in mammals, enzymes that catalyze the later steps of this pathway are considered a target for antifungal drugs [Nagiec97, Sugimoto04].

Variants: ceramide de novo biosynthesis, ceramide phosphoethanolamine biosynthesis, sphingolipid biosynthesis (mammals), sphingolipid biosynthesis (plants)

Created 21-Dec-2004 by Hong E, Saccharomyces Genome Database
Revised 26-Sep-2012 by Caspi R, SRI International


Bagnat02: Bagnat M, Simons K (2002). "Lipid rafts in protein sorting and cell polarity in budding yeast Saccharomyces cerevisiae." Biol Chem 383(10);1475-80. PMID: 12452424

Dickson02: Dickson RC, Lester RL (2002). "Sphingolipid functions in Saccharomyces cerevisiae." Biochim Biophys Acta 1583(1);13-25. PMID: 12069845

FergusonYankey02: Ferguson-Yankey SR, Skrzypek MS, Lester RL, Dickson RC (2002). "Mutant analysis reveals complex regulation of sphingolipid long chain base phosphates and long chain bases during heat stress in yeast." Yeast 19(7);573-86. PMID: 11967828

Funato02: Funato K, Vallee B, Riezman H (2002). "Biosynthesis and trafficking of sphingolipids in the yeast Saccharomyces cerevisiae." Biochemistry 41(51);15105-14. PMID: 12484746

Jenkins97: Jenkins GM, Richards A, Wahl T, Mao C, Obeid L, Hannun Y (1997). "Involvement of yeast sphingolipids in the heat stress response of Saccharomyces cerevisiae." J Biol Chem 272(51);32566-72. PMID: 9405471

Kobayashi03: Kobayashi SD, Nagiec MM (2003). "Ceramide/long-chain base phosphate rheostat in Saccharomyces cerevisiae: regulation of ceramide synthesis by Elo3p and Cka2p." Eukaryot Cell 2(2);284-94. PMID: 12684378

Nagiec97: Nagiec MM, Nagiec EE, Baltisberger JA, Wells GB, Lester RL, Dickson RC (1997). "Sphingolipid synthesis as a target for antifungal drugs. Complementation of the inositol phosphorylceramide synthase defect in a mutant strain of Saccharomyces cerevisiae by the AUR1 gene." J Biol Chem 272(15);9809-17. PMID: 9092515

Sugimoto04: Sugimoto Y, Sakoh H, Yamada K (2004). "IPC synthase as a useful target for antifungal drugs." Curr Drug Targets Infect Disord 4(4);311-22. PMID: 15578972

Thudichum84: Thudichum, J. L. W. (1884). "A Treatise on the Chemical Constitution of Brain." Bailliere, Tindall, and Cox, London.

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

Beeler97: Beeler TJ, Fu D, Rivera J, Monaghan E, Gable K, Dunn TM (1997). "SUR1 (CSG1/BCL21), a gene necessary for growth of Saccharomyces cerevisiae in the presence of high Ca2+ concentrations at 37 degrees C, is required for mannosylation of inositolphosphorylceramide." Mol Gen Genet 255(6);570-9. PMID: 9323360

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

Buede91: Buede R, Rinker-Schaffer C, Pinto WJ, Lester RL, Dickson RC (1991). "Cloning and characterization of LCB1, a Saccharomyces gene required for biosynthesis of the long-chain base component of sphingolipids." J Bacteriol 173(14);4325-32. PMID: 2066332

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

Cliften96: Cliften P, Wang Y, Mochizuki D, Miyakawa T, Wangspa R, Hughes J, Takemoto JY (1996). "SYR2, a gene necessary for syringomycin growth inhibition of Saccharomyces cerevisiae." Microbiology 142 ( Pt 3);477-84. PMID: 8868422

Cowart07: Cowart LA, Obeid LM (2007). "Yeast sphingolipids: recent developments in understanding biosynthesis, regulation, and function." Biochim Biophys Acta 1771(3);421-31. PMID: 16997623

Dean97: Dean N, Zhang YB, Poster JB (1997). "The VRG4 gene is required for GDP-mannose transport into the lumen of the Golgi in the yeast, Saccharomyces cerevisiae." J Biol Chem 272(50);31908-14. PMID: 9395539

Desfarges93: Desfarges L, Durrens P, Juguelin H, Cassagne C, Bonneu M, Aigle M (1993). "Yeast mutants affected in viability upon starvation have a modified phospholipid composition." Yeast 9(3);267-77. PMID: 8488727

Dey97: Dey, P. M., Harborne, J. B. (1997). "Plant Biochemistry." Academic Press Inc., San Diego, USA.

Dickson90: Dickson RC, Wells GB, Schmidt A, Lester RL (1990). "Isolation of mutant Saccharomyces cerevisiae strains that survive without sphingolipids." Mol Cell Biol 10(5);2176-81. PMID: 2183021

Dickson97: Dickson RC, Nagiec EE, Wells GB, Nagiec MM, Lester RL (1997). "Synthesis of mannose-(inositol-P)2-ceramide, the major sphingolipid in Saccharomyces cerevisiae, requires the IPT1 (YDR072c) gene." J Biol Chem 272(47);29620-5. PMID: 9368028

Dickson97a: Dickson RC, Nagiec EE, Skrzypek M, Tillman P, Wells GB, Lester RL (1997). "Sphingolipids are potential heat stress signals in Saccharomyces." J Biol Chem 272(48);30196-200. PMID: 9374502

Dickson99: Dickson RC, Lester RL (1999). "Yeast sphingolipids." Biochim Biophys Acta 1426(2);347-57. PMID: 9878820

Dunn98: Dunn TM, Haak D, Monaghan E, Beeler TJ (1998). "Synthesis of monohydroxylated inositolphosphorylceramide (IPC-C) in Saccharomyces cerevisiae requires Scs7p, a protein with both a cytochrome b5-like domain and a hydroxylase/desaturase domain." Yeast 14(4);311-21. PMID: 9559540

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

Grilley00: Grilley MM, Takemoto JY (2000). "Assay of the Saccharomyces cerevisiae dihydrosphingosine C-4 hydroxylase." Methods Enzymol 311;9-14. PMID: 10563305

Grilley98: Grilley MM, Stock SD, Dickson RC, Lester RL, Takemoto JY (1998). "Syringomycin action gene SYR2 is essential for sphingolipid 4-hydroxylation in Saccharomyces cerevisiae." J Biol Chem 273(18);11062-8. PMID: 9556590

Guillas01: Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, Jazwinski SM, Conzelmann A (2001). "C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p." EMBO J 20(11);2655-65. PMID: 11387200

Guo12a: Guo L, Zhang X, Zhou D, Okunade AL, Su X (2012). "Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2-hydroxy fatty acid enantiomers." J Lipid Res 53(7);1327-35. PMID: 22517924

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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.