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MetaCyc Pathway: zymosterol biosynthesis
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: zymosterol 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 BiosynthesisSterol Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Saccharomyces cerevisiae

Expected Taxonomic Range: Opisthokonta

zymosterol is an intermediate in the biosynthesis of both ergosterol, a major constituent of the fungal plasma membrane [Paltauf92, Parks95], and cholesterol, the homologous component in mammalian membranes. cholesterol and ergosterol share most of their biosynthetic pathway, with differences only in the part of the pathway that is downstream of zymosterol.

In the first part of this pathway, starting at lanosterol, a sequence of two enzymatic reactions, involving cytochrome P450 51, and C-14 sterol reductase, converts this tetracyclic triterpenoid to the sterol intermediate 4,4-dimethylzymosterol. In the second part of the pathway, a set of three enzymes removes two methyl groups from the A ring of 4,4-dimethylzymosterol, resulting in formation of zymosterol.

The demethylation sequence starts with C-4 methyl sterol oxidase. This enzyme acts in three steps - it first adds a hydroxyl group to the methyl carbon, converting it to a hydroxylmethyl group. It continues by oxidation of the hydroxyl moiety resulting in a formyl group, and ends with the addition of a second hydroxyl group, generating a carboxyl group. This carboxyl is then removed by the second enzyme, C-3 sterol dehydrogenase. In the process of decarboxylation, a hydroxyl group attached to another carbon of the sterol ring is oxidized to a keto group, and in order to complete this cycle, the third enzyme, 3-keto sterol reductase, restores it back to the initial hydroxyl group.

When the first cycle is complete, 4,4-dimethylzymosterol has been converted to 4α-methyl-zymosterol, which is the substrate for a second round of activity. When the second cycle is complete, 4α-methyl-zymosterol has been converted to zymosterol.

This pathway has been the subject of intensive investigation as a target of antifungal drugs [Lupetti02]. cytochrome P450 51, a member of the cytochrome P450 family encoded by the ERG11 gene, is the major target of azole antifungal drugs [Leber03].

Superpathways: superpathway of ergosterol biosynthesis I

Created 29-Oct-2008 by Caspi R, SRI International


Leber03: Leber R, Fuchsbichler S, Klobucnikova V, Schweighofer N, Pitters E, Wohlfarter K, Lederer M, Landl K, Ruckenstuhl C, Hapala I, Turnowsky F (2003). "Molecular mechanism of terbinafine resistance in Saccharomyces cerevisiae." Antimicrob Agents Chemother 47(12);3890-900. PMID: 14638499

Lupetti02: Lupetti A, Danesi R, Campa M, Del Tacca M, Kelly S (2002). "Molecular basis of resistance to azole antifungals." Trends Mol Med 8(2);76-81. PMID: 11815273

Paltauf92: Paltauf, F, Kohlwein, S, Henry, SA (1992). "Regulation and compartmentalization of lipid synthesis in yeast." The Molecular and Cellular Biology of the yeastSaccharomyces: Gene Expression, Vol. 2, pp.415 - 500.

Parks95: Parks LW, Casey WM (1995). "Physiological implications of sterol biosynthesis in yeast." Annu Rev Microbiol 49;95-116. PMID: 8561481

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

Aoyama83: Aoyama Y, Yoshida Y, Hata S, Nishino T, Katsuki H (1983). "Buthiobate: a potent inhibitor for yeast cytochrome P-450 catalyzing 14 alpha-demethylation of lanosterol." Biochem Biophys Res Commun 115(2);642-7. PMID: 6414474

Aoyama94: Aoyama Y, Funae Y, Noshiro M, Horiuchi T, Yoshida Y (1994). "Occurrence of a P450 showing high homology to yeast lanosterol 14-demethylase (P450(14DM)) in the rat liver." Biochem Biophys Res Commun 201(3);1320-6. PMID: 8024575

Aoyama96: Aoyama Y, Noshiro M, Gotoh O, Imaoka S, Funae Y, Kurosawa N, Horiuchi T, Yoshida Y (1996). "Sterol 14-demethylase P450 (P45014DM*) is one of the most ancient and conserved P450 species." J Biochem (Tokyo) 119(5);926-33. PMID: 8797093

Bard96: Bard M, Bruner DA, Pierson CA, Lees ND, Biermann B, Frye L, Koegel C, Barbuch R (1996). "Cloning and characterization of ERG25, the Saccharomyces cerevisiae gene encoding C-4 sterol methyl oxidase." Proc Natl Acad Sci U S A 93(1);186-90. PMID: 8552601

Caldas03: Caldas H, Herman GE (2003). "NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets." Hum Mol Genet 12(22);2981-91. PMID: 14506130

Crowley96: Crowley JH, Smith SJ, Leak FW, Parks LW (1996). "Aerobic isolation of an ERG24 null mutant of Saccharomyces cerevisiae." J Bacteriol 178(10);2991-3. PMID: 8631695

Gachotte98: Gachotte D, Barbuch R, Gaylor J, Nickel E, Bard M (1998). "Characterization of the Saccharomyces cerevisiae ERG26 gene encoding the C-3 sterol dehydrogenase (C-4 decarboxylase) involved in sterol biosynthesis." Proc Natl Acad Sci U S A 95(23);13794-9. PMID: 9811880

Gachotte99: Gachotte D, Sen SE, Eckstein J, Barbuch R, Krieger M, Ray BD, Bard M (1999). "Characterization of the Saccharomyces cerevisiae ERG27 gene encoding the 3-keto reductase involved in C-4 sterol demethylation." Proc Natl Acad Sci U S A 96(22);12655-60. PMID: 10535978

Gaylor75: Gaylor JL, Miyake Y, Yamano T (1975). "Stoichiometry of 4-methyl sterol oxidase of rat liver microsomes." J Biol Chem 250(18);7159-67. PMID: 240818

Halder02: Halder SK, Fink M, Waterman MR, Rozman D (2002). "A cAMP-responsive element binding site is essential for sterol regulation of the human lanosterol 14alpha-demethylase gene (CYP51)." Mol Endocrinol 16(8);1853-63. PMID: 12145339

Hata83: Hata S, Nishino T, Katsuki H, Aoyama Y, Yoshida Y (1983). "Two species of cytochrome P-450 involved in ergosterol biosynthesis of yeast." Biochem Biophys Res Commun 116(1);162-6. PMID: 6357195

Herman03: Herman GE (2003). "Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes." Hum Mol Genet 12 Spec No 1;R75-88. PMID: 12668600

Hoffmann02: Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, Karl H, Kaps R, Muller D, Vaya A, Aznar J, Ware RE, Sotelo Cruz N, Lindner TH, Herrmann H, Reis A, Sperling K (2002). "Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly)." Nat Genet 31(4);410-4. PMID: 12118250

Holmer98: Holmer L, Pezhman A, Worman HJ (1998). "The human lamin B receptor/sterol reductase multigene family." Genomics 54(3);469-76. PMID: 9878250

Huang01: Huang XF, Luu-The V (2001). "Gene structure, chromosomal localization and analysis of 3-ketosteroid reductase activity of the human 3(alpha-->beta)-hydroxysteroid epimerase." Biochim Biophys Acta 1520(2);124-30. PMID: 11513953

Kalb86: Kalb VF, Loper JC, Dey CR, Woods CW, Sutter TR (1986). "Isolation of a cytochrome P-450 structural gene from Saccharomyces cerevisiae." Gene 45(3);237-45. PMID: 3542713

Kalb87: Kalb VF, Woods CW, Turi TG, Dey CR, Sutter TR, Loper JC (1987). "Primary structure of the P450 lanosterol demethylase gene from Saccharomyces cerevisiae." DNA 6(6);529-37. PMID: 3322742

Konig00: Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH (2000). "Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome." Am J Med Genet 90(4);339-46. PMID: 10710235

Krazeisen99: Krazeisen A, Breitling R, Imai K, Fritz S, Moller G, Adamski J (1999). "Determination of cDNA, gene structure and chromosomal localization of the novel human 17beta-hydroxysteroid dehydrogenase type 7(1)." FEBS Lett 460(2);373-9. PMID: 10544267

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

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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 Sat Apr 30, 2016, biocyc11.