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Pathway Description
Cholesterol Biosynthesis and Metabolism CE(14:0)
Saccharomyces cerevisiae
Metabolic Pathway
The biosynthesis of Cholesterol starts with acetyl-CoA reacts with acetyl-CoA c-acetyltransferase resulting in the release of CoA acetoacetyl-CoA, The latter compound then reacts with an acetyl-coa through a hydroxymethylglutaryl-CoA synthase resulting in the release of 3-hydroxy-3-methylglutaryl-CoA. The latter compound in turn reacts with a NADPH through a 3-hydroxy-3-methylglutaryl-coenzyme A reductase resulting in the release of a NADP, Coenzyme A and Mevalonic acid. The latter is then phosphorylated by ATP through a mevalonate kinase resulting in the release of ADP and Mevalonic acid-5P which is then phosphorylated by ATP through a phosphomevalonate kinase resulting in the release of ADP and (S)-5-diphosphomevalonic acid. The latter compound in turn reacts with ATP through a diphosphomevalonic decarboxylase resulting in the release of phosphate, ADP, carbon dioxide and Isopentenyl pyrophosphate. The latter compound in turn reacts with isopentenyl diphosphate delta isomerase resulting in the release of dimethylallylpyrophosphate. The latter compound then reacts with isopentenyl pyrophosphate through a farnesyl pyrophosphate synthase resulting in the release of Geranyl-PP. The latter then reacts with an isopentenyl pyrophosphate through farnesyl pyrophosphate synthase resulting in the release of pyrophospate and farnesyl pyrophosphate. Farnesyl pyrophosphate then reacts with NADPH through a squalene synthase in order to produce squalene while also releasing two phosphates and NADP. Squalene then reacts with oxygen and NADPH through a squalene monooxygenase resulting in the release of water, NADP and (S)-2,3-epoxysqualene. The latter in turn reacts with lanosterol synthase resulting in the release of lanosterin. Lanosterin then reacts with oxygen and NADPH through a lanosterol 14-alpha demethylase resulting in the release of formic acid, water, NADP and 4,4-dimethylcholesta-8,14,24-trienol. The latter compound in turn is reduced by an NADPH through a Delta (14)-sterol reductase resulting in the release of NADP and 4,4-dimethyl-5a-cholesta-8,24-dien-3-b-ol. The latter reacts with hydrogen ion,oxygen and NADPH through a methylsterol monooxygenase resulting in the release of NADP, water and 4a-hydroxymethyl-4B-methyl-5a-cholesta-8,24-dien-3B-ol. The latter compound reacts with a hydrogen ion, water, and NADPH through a methylsterol monooxygenase resulting in the release of NADP, water and 4a-formyl-4b-methyl-5a-cholesta-8,24-dien-3B-ol. The latter reacts with oxygen, NADPH through methylsterol monooxygenase resulting in the release of water, NADP and 4B-methyl-4a-carboxy-cholesta-8,24-dien-3B-ol. The latter reacts with an NADP through c-3 sterol dehydrogenase resulting in the release of NADPH, carbon dioxide and 3-keto-4-methylzymosterol. The latter is reduced by NADPH through a 3-keto sterol reductase resulting in the release of NADP and 4a-methylzymosterol. The latter then reacts with hydrogen, oxygen and nadph through methylsterol monooxygenase resulting in the release of water, NADP and 4a-hydroxymethyl-5a-cholesta-8,24-dien-3B-ol. The latter reacts with water, hydrogen and NADPH through a methylsterol monooxygenase resulting in the release of water, NADP and 4a-formyl-5a-cholesta-8,24-dien-3B-ol. The latter reacts with oxygen and NADPH through methylsterol monooxygenase resulting in the release of water, NADP and 4a-carboxy-5a-cholesta-8,24-dien-3B-ol. The latter compound reacts with NADP through a C-3 sterol dehydrogenase resulting in the release of carbon dioxide, NADPH and 5a-cholesta-8,24-dien-3-one. The latter reacts with hydrogen ion and NADPH through a 3-keto sterol reductase resulting in the release of NADP and zymosterol. Zymosterol can either be used to create ergosterol starts with zymosterol reacting with S-adenosylmethionine through a sterol 24-c-methyltransferase resulting in the release of S-adenosylhomocysteine, hydrogen ion and fecosterol. Fecosterol reacts with C-8 sterol isomerase resulting in the release of episterol. Episterol reacts with oxygen, hydrogen ion and ferrocytochrome c through a C-5 sterol desaturase resulting in the release of ferricytochrome c, water and 5,7,24(28)-ergostatrienol. The latter reacts with hydrogen ion, oxygen, NADPH and c-22 sterol desaturase resulting in the release of water, NADP AND ERGOSTA-5,7,22,24(28)-tetraen-3-B-ol. The latter compound reacts with hydrogen ion and NADPH through a C-24 sterol reductase resulting in the release of NADP and ergosterol. Zymosterol reacts with C-8 sterol isomerase resulting in the release of 5a-cholesta-7,24-dien-3b-ol. The latter compound reacts with C-5 sterol desaturase resulting in the release of 7-dehydrodesmosterol. The latter is then converted spontaneously through desmosterol. Desmosterol is then spontaneously turned into cholesterol which can in turn react with tetradecanoyl-CoA spontaneously resulting in the release of Coenzyme A and CE(14:0).
References
Cholesterol Biosynthesis and Metabolism CE(14:0) References
Bard M, Lees ND, Turi T, Craft D, Cofrin L, Barbuch R, Koegel C, Loper JC: Sterol synthesis and viability of erg11 (cytochrome P450 lanosterol demethylase) mutations in Saccharomyces cerevisiae and Candida albicans. Lipids. 1993 Nov;28(11):963-7.
Pubmed: 8277826
Kaneshiro ES: Sterol biosynthesis in Pneumocystis: unique steps that define unique targets. Drug Resist Updat. 2002 Dec;5(6):259-68.
Pubmed: 12531182
Palermo LM, Leak FW, Tove S, Parks LW: Assessment of the essentiality of ERG genes late in ergosterol biosynthesis in Saccharomyces cerevisiae. Curr Genet. 1997 Aug;32(2):93-9.
Pubmed: 9294256
Paltauf, F, Kohlwein, S, Henry, SA. Regulation and compartmentalization of lipid synthesis in yeast. The Molecular and Cellular Biology of the yeast Saccharomyces: Gene Expression. 1992;2:415-500.
Parks LW, Casey WM: Physiological implications of sterol biosynthesis in yeast. Annu Rev Microbiol. 1995;49:95-116. doi: 10.1146/annurev.mi.49.100195.000523.
Pubmed: 8561481
Arthington BA, Hoskins J, Skatrud PL, Bard M: Nucleotide sequence of the gene encoding yeast C-8 sterol isomerase. Gene. 1991 Oct 30;107(1):173-4.
Pubmed: 1743517
Arthington BA, Bennett LG, Skatrud PL, Guynn CJ, Barbuch RJ, Ulbright CE, Bard M: Cloning, disruption and sequence of the gene encoding yeast C-5 sterol desaturase. Gene. 1991 Jun 15;102(1):39-44.
Pubmed: 1864507
Ashman WH, Barbuch RJ, Ulbright CE, Jarrett HW, Bard M: Cloning and disruption of the yeast C-8 sterol isomerase gene. Lipids. 1991 Aug;26(8):628-32.
Pubmed: 1779709
Bard M: Biochemical and genetic aspects of nystatin resistance in saccharomyces cerevisiae. J Bacteriol. 1972 Sep;111(3):649-57.
Pubmed: 4559817
Hata S, Nishino T, Katsuki H, Aoyama Y, Yoshida Y: Two species of cytochrome P-450 involved in ergosterol biosynthesis of yeast. Biochem Biophys Res Commun. 1983 Oct 14;116(1):162-6.
Pubmed: 6357195
He X, Zhang B, Tan H: Overexpression of a sterol C-24(28) reductase increases ergosterol production in Saccharomyces cerevisiae. Biotechnol Lett. 2003 May;25(10):773-8.
Pubmed: 12882006
Kelly SL, Lamb DC, Corran AJ, Baldwin BC, Parks LW, Kelly DE: Purification and reconstitution of activity of Saccharomyces cerevisiae P450 61, a sterol delta 22-desaturase. FEBS Lett. 1995 Dec 18;377(2):217-20.
Pubmed: 8543054
McCammon MT, Hartmann MA, Bottema CD, Parks LW: Sterol methylation in Saccharomyces cerevisiae. J Bacteriol. 1984 Feb;157(2):475-83.
Pubmed: 6363386
Molzahn SW, Woods RA: Polyene resistance and the isolation of sterol mutants in Saccharomyces cerevisiae. J Gen Microbiol. 1972 Sep;72(2):339-48. doi: 10.1099/00221287-72-2-339.
Pubmed: 4562308
Moore JT, Gaylor JL: Isolation and purification of an S-adenosylmethionine: delta 24-sterol methyltransferase from yeast. J Biol Chem. 1969 Dec 10;244(23):6334-40.
Pubmed: 5354959
Leber R, Fuchsbichler S, Klobucnikova V, Schweighofer N, Pitters E, Wohlfarter K, Lederer M, Landl K, Ruckenstuhl C, Hapala I, Turnowsky F: Molecular mechanism of terbinafine resistance in Saccharomyces cerevisiae. Antimicrob Agents Chemother. 2003 Dec;47(12):3890-900.
Pubmed: 14638499
Bard M, Bruner DA, Pierson CA, Lees ND, Biermann B, Frye L, Koegel C, Barbuch R: Cloning and characterization of ERG25, the Saccharomyces cerevisiae gene encoding C-4 sterol methyl oxidase. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):186-90.
Pubmed: 8552601
Crowley JH, Smith SJ, Leak FW, Parks LW: Aerobic isolation of an ERG24 null mutant of Saccharomyces cerevisiae. J Bacteriol. 1996 May;178(10):2991-3.
Pubmed: 8631695
Gachotte D, Barbuch R, Gaylor J, Nickel E, Bard M: 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. 1998 Nov 10;95(23):13794-9.
Pubmed: 9811880
Gachotte D, Sen SE, Eckstein J, Barbuch R, Krieger M, Ray BD, Bard M: 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. 1999 Oct 26;96(22):12655-60.
Pubmed: 10535978
Milla P, Athenstaedt K, Viola F, Oliaro-Bosso S, Kohlwein SD, Daum G, Balliano G: Yeast oxidosqualene cyclase (Erg7p) is a major component of lipid particles. J Biol Chem. 2002 Jan 25;277(4):2406-12. doi: 10.1074/jbc.M104195200. Epub 2001 Nov 12.
Pubmed: 11706015
This pathway was generated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Generated from PW071057
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