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.
Synonyms: superpathway of ergosterol biosynthesis I (fungi)
|Superclasses:||Biosynthesis → Fatty Acid and Lipid Biosynthesis → Sterol Biosynthesis → Ergosterol Biosynthesis|
Some taxa known to possess this pathway include : Saccharomyces cerevisiae
Expected Taxonomic Range: Fungi
ergosterol is a major constituent of the fungal plasma membrane [Paltauf92, Parks95]. Only the very last part of this pathway (starting at zymosterol) is fungal-specific. Most of the pathway is shared between yeast and other organisms whose plasma membranes are composed predominantly of other types of sterols, (e.g. cholesterol).
This superpathway describes the complete pathway for the synthesis of ergosterol from the central metabolite acetyl-CoA. It includes several subpathways, including the mevalonate pathway I, which describes the synthesis of the isopreoid building blocks dimethylallyl diphosphate and isopentenyl diphosphate, trans, trans-farnesyl diphosphate biosynthesis, which describes the synthesis of this central intermediate, which feeds into many different metabolic routes, epoxysqualene biosynthesis, which describes the first committed step for the synthesis of sterols, generating (3S)-2,3-epoxy-2,3-dihydrosqualene, and finally the pathways for zymosterol biosynthesis and ergosterol biosynthesis I.
In Saccharomyces cerevisiae, some of the steps in the pathway are essential for viability [Bard93]. As a result, this pathway has been the subject of intensive investigation as a target of antifungal drugs [Lupetti02]. The major target of azole antifungal drugs is cytochrome P450 51, a member of the cytochrome P450 family encoded by the gene ERG11. The specific target of allylamine drugs such as terbinafine (known as Lamisil) is squalene monooxygenase, encoded by the ERG1 gene [Leber03]. Mutations in the genes encoding these enzymes and others in the pathway, as well as alterations in the expression levels of the pathway constituents, can lead to antifungal drug resistance [Lupetti02].
Bard93: Bard M, Lees ND, Turi T, Craft D, Cofrin L, Barbuch R, Koegel C, Loper JC (1993). "Sterol synthesis and viability of erg11 (cytochrome P450 lanosterol demethylase) mutations in Saccharomyces cerevisiae and Candida albicans." Lipids 28(11);963-7. PMID: 8277826
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
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.
Aharoni03: Aharoni A, Giri AP, Deuerlein S, Griepink F, de Kogel WJ, Verstappen FW, Verhoeven HA, Jongsma MA, Schwab W, Bouwmeester HJ (2003). "Terpenoid metabolism in wild-type and transgenic Arabidopsis plants." Plant Cell 15(12);2866-84. PMID: 14630967
Alber06: Alber BE, Spanheimer R, Ebenau-Jehle C, Fuchs G (2006). "Study of an alternate glyoxylate cycle for acetate assimilation by Rhodobacter sphaeroides." Mol Microbiol 61(2);297-309. PMID: 16856937
Anderson89: Anderson MS, Muehlbacher M, Street IP, Proffitt J, Poulter CD (1989). "Isopentenyl diphosphate:dimethylallyl diphosphate isomerase. An improved purification of the enzyme and isolation of the gene from Saccharomyces cerevisiae." J Biol Chem 1989;264(32);19169-75. PMID: 2681212
Anderson89a: Anderson MS, Yarger JG, Burck CL, Poulter CD (1989). "Farnesyl diphosphate synthetase. Molecular cloning, sequence, and expression of an essential gene from Saccharomyces cerevisiae." J Biol Chem 1989;264(32);19176-84. PMID: 2681213
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
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
Arthington91: Arthington BA, Bennett LG, Skatrud PL, Guynn CJ, Barbuch RJ, Ulbright CE, Bard M (1991). "Cloning, disruption and sequence of the gene encoding yeast C-5 sterol desaturase." Gene 102(1);39-44. PMID: 1864507
Balliano92: Balliano G, Viola F, Ceruti M, Cattel L (1992). "Characterization and partial purification of squalene-2,3-oxide cyclase from Saccharomyces cerevisiae." Arch Biochem Biophys 293(1);122-9. PMID: 1731628
Bard81: Bard M, Downing JF (1981). "Genetic and biochemical aspects of yeast sterol regulation involving 3-hydroxy-3-methylglutaryl coenzyme A reductase." J Gen Microbiol 1981;125(Pt 2);415-20. PMID: 7033470
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
Basson86: Basson ME, Thorsness M, Rine J (1986). "Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase." Proc Natl Acad Sci U S A 1986;83(15);5563-7. PMID: 3526336
Berges97: Berges T, Guyonnet D, Karst F (1997). "The Saccharomyces cerevisiae mevalonate diphosphate decarboxylase is essential for viability, and a single Leu-to-Pro mutation in a conserved sequence leads to thermosensitivity." J Bacteriol 1997;179(15);4664-70. PMID: 9244250
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