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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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MetaCyc Pathway: cholesterol biosynthesis II (via 24,25-dihydrolanosterol)

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 Sterol Biosynthesis
Superpathways

Some taxa known to possess this pathway include ? : Homo sapiens

Expected Taxonomic Range: Metazoa

Summary:
The sequence of reactions in the cholesterol biosynthetic pathway may vary. This pathway shows one possible variant of cholesterol biosynthesis. This and other alternate routes exist because reduction of the carbon 24,25 double bond on the hydrocarbon side chain of the sterol ring structure by sterol Δ24-reductase can occur at multiple points in the pathway, giving rise to different intermediates. These intermediates, with or without a double bond in the hydrocarbon side chain, can serve as substrates for the other enzymes in the pathway. However, there is evidence that the preferred point of carbon 24,25 double bond reduction is directly after the isomerization of zymosterol [Bae97], as shown in pathway cholesterol biosynthesis I. In [Waterham01] and reviewed in [Gaylor02].

In the pathway shown here reduction of the carbon 24,25 double bond in the hydrocarbon side chain occurs at the point of lanosterol, producing 24,25-dihydrolanosterol. This compound is a substrate for the next enzyme in the pathway lanosterol 14 α-demethylase (cytochrome P450 51 protein) (reviewed in [Gaylor02], in [Aoyama91, Nes, Sonoda88, AVIGAN63]). Carbon monoxide has been shown to inhibit this enzyme, causing lanosterol and 24,25-dihydrolanosterol to accumulate [Gibbons72, Bae97] . The antimycotic drugs ketoconazole and miconazole have also been shown to inhibit lanosterol 14 α-demethylase, resulting in an accumulation of 24,25-dihydrolanosterol [Raucy91, Bae97, Miettinen88]. Other azoles, oxygenated lanosterol derivatives, and their analogs, that inhibit this enzyme (as well as HMG-CoA reductase from the mevalonate pathway I) have been studied as possible cholesterol-lowering drugs [Trzaskos95, Sonoda88, Swinney94, Tuck91].

Superpathways: superpathway of cholesterol biosynthesis

Subpathways: lanosterol biosynthesis , epoxysqualene biosynthesis


References

Aoyama91: Aoyama Y, Yoshida Y (1991). "Different substrate specificities of lanosterol 14a-demethylase (P-45014DM) of Saccharomyces cerevisiae and rat liver for 24-methylene-24,25-dihydrolanosterol and 24,25-dihydrolanosterol." Biochem Biophys Res Commun 178(3);1064-71. PMID: 1872829

AVIGAN63: AVIGAN J, GOODMAN DS, STEINBERG D (1963). "Studies of cholesterol biosynthesis. IV. Reduction of lanosterol to 24,25-dihydrolanosterol by rat liver homogenates." J Biol Chem 238;1283-6. PMID: 13965665

Bae97: Bae SH, Paik YK (1997). "Cholesterol biosynthesis from lanosterol: development of a novel assay method and characterization of rat liver microsomal lanosterol delta 24-reductase." Biochem J 326 ( Pt 2);609-16. PMID: 9291139

Buttke92: Buttke TM, Folks TM (1992). "Complete replacement of membrane cholesterol with 4,4',14-trimethyl sterols in a human T cell line defective in lanosterol demethylation." J Biol Chem 267(13);8819-26. PMID: 1577721

Gaylor02: Gaylor JL (2002). "Membrane-bound enzymes of cholesterol synthesis from lanosterol." Biochem Biophys Res Commun 292(5);1139-46. PMID: 11969204

Gibbons72: Gibbons GF, Mitropoulos KA (1972). "Inhibition of cholesterol biosynthesis by carbon monoxide: accumulation of lanosterol and 24,25-dihydrolanosterol." Biochem J 127(1);315-7. PMID: 5073750

Kraemer86: Kraemer FB, Spilman SD (1986). "Effects of ketoconazole on cholesterol synthesis." J Pharmacol Exp Ther 238(3);905-11. PMID: 3746668

Megha06: Megha , Bakht O, London E (2006). "Cholesterol precursors stabilize ordinary and ceramide-rich ordered lipid domains (lipid rafts) to different degrees. Implications for the Bloch hypothesis and sterol biosynthesis disorders." J Biol Chem 281(31);21903-13. PMID: 16735517

Miettinen88: Miettinen TA (1988). "Cholesterol metabolism during ketoconazole treatment in man." J Lipid Res 29(1);43-51. PMID: 3356951

Nes: Nes WD, Norton RA, Parish EJ, Meenan A, Popjak G "Concerning the role of 24,25-dihydrolanosterol and lanostanol in sterol biosynthesis by cultured cells." Steroids 53(3-5);461-75. PMID: 2799854

Raucy91: Raucy JL, Carpenter SJ, Trzaskos JM (1991). "Identification of lanosterol 14 alpha-methyl demethylase in human tissues." Biochem Biophys Res Commun 177(1);497-503. PMID: 2043135

Salway04a: Salway JG (2004). "Metabolism at a Glance." 3rd ed, Blackwell Publishing, Malden, MA, USA.

Sonoda88: Sonoda Y, Sekigawa Y, Sato Y (1988). "In vitro effects of oxygenated lanosterol derivatives on cholesterol biosynthesis from 24,25-dihydrolanosterol." Chem Pharm Bull (Tokyo) 36(3);966-73. PMID: 3409414

Swinney94: Swinney DC, So OY, Watson DM, Berry PW, Webb AS, Kertesz DJ, Shelton EJ, Burton PM, Walker KA (1994). "Selective inhibition of mammalian lanosterol 14 alpha-demethylase by RS-21607 in vitro and in vivo." Biochemistry 33(15);4702-13. PMID: 8161528

Trzaskos95: Trzaskos JM, Ko SS, Magolda RL, Favata MF, Fischer RT, Stam SH, Johnson PR, Gaylor JL (1995). "Substrate-based inhibitors of lanosterol 14 alpha-methyl demethylase: I. Assessment of inhibitor structure-activity relationship and cholesterol biosynthesis inhibition properties." Biochemistry 34(30);9670-6. PMID: 7626636

Tuck91: Tuck SF, Patel H, Safi E, Robinson CH (1991). "Lanosterol 14 alpha-demethylase (P45014DM): effects of P45014DM inhibitors on sterol biosynthesis downstream of lanosterol." J Lipid Res 32(6);893-902. PMID: 1940622

Waterham01: Waterham HR, Koster J, Romeijn GJ, Hennekam RC, Vreken P, Andersson HC, FitzPatrick DR, Kelley RI, Wanders RJ (2001). "Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis." Am J Hum Genet 69(4);685-94. PMID: 11519011

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

Abe94: Abe I, Tomesch JC, Wattanasin S, Prestwich GD (1994). "Inhibitors of squalene biosynthesis and metabolism." Nat Prod Rep 11(3);279-302. PMID: 15200015

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

Baker95a: Baker CH, Matsuda SP, Liu DR, Corey EJ (1995). "Molecular cloning of the human gene encoding lanosterol synthase from a liver cDNA library." Biochem Biophys Res Commun 213(1);154-60. PMID: 7639730

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

Billheimer81: Billheimer JT, Alcorn M, Gaylor JL (1981). "Solubilization and partial purification of a microsomal 3-ketosteroid reductase of cholesterol biosynthesis." Arch Biochem Biophys 211(1);430-8. PMID: 6946726

Bloch65: Bloch K (1965). "The biological synthesis of cholesterol." Science 150(692);19-28. PMID: 5319508

Bloch92: Bloch K (1992). "Sterol molecule: structure, biosynthesis, and function." Steroids 57(8);378-83. PMID: 1519268

Bode03: Bode HB, Zeggel B, Silakowski B, Wenzel SC, Reichenbach H, Muller R (2003). "Steroid biosynthesis in prokaryotes: identification of myxobacterial steroids and cloning of the first bacterial 2,3(S)-oxidosqualene cyclase from the myxobacterium Stigmatella aurantiaca." Mol Microbiol 47(2);471-81. PMID: 12519197

Braverman99: Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, Wilcox WR, Rimoin DL, Smith M, Kratz L, Kelley RI, Valle D (1999). "Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hunermann syndrome." Nat Genet 22(3);291-4. PMID: 10391219

BrunettiPierri02: Brunetti-Pierri N, Corso G, Rossi M, Ferrari P, Balli F, Rivasi F, Annunziata I, Ballabio A, Russo AD, Andria G, Parenti G (2002). "Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase." Am J Hum Genet 71(4);952-8. PMID: 12189593

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

Diener00: Diener AC, Li H, Zhou W, Whoriskey WJ, Nes WD, Fink GR (2000). "Sterol methyltransferase 1 controls the level of cholesterol in plants." Plant Cell 12(6);853-70. PMID: 10852933

Fitzky98: Fitzky BU, Witsch-Baumgartner M, Erdel M, Lee JN, Paik YK, Glossmann H, Utermann G, Moebius FF (1998). "Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome." Proc Natl Acad Sci U S A 95(14);8181-6. PMID: 9653161

Fukushima81: Fukushima H, Grinstead GF, Gaylor JL (1981). "Total enzymic synthesis of cholesterol from lanosterol. Cytochrome b5-dependence of 4-methyl sterol oxidase." J Biol Chem 256(10);4822-6. PMID: 7228857

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

Greeve00: Greeve I, Hermans-Borgmeyer I, Brellinger C, Kasper D, Gomez-Isla T, Behl C, Levkau B, Nitsch RM (2000). "The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress." J Neurosci 20(19);7345-52. PMID: 11007892

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

Hanner95: Hanner M, Moebius FF, Weber F, Grabner M, Striessnig J, Glossmann H (1995). "Phenylalkylamine Ca2+ antagonist binding protein. Molecular cloning, tissue distribution, and heterologous expression." J Biol Chem 270(13);7551-7. PMID: 7706302

Hattori00: Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML, (2000). "The DNA sequence of human chromosome 21." Nature 405(6784);311-9. PMID: 10830953

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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 SRI International Pathway Tools version 18.5 on Sat Dec 20, 2014, biocyc12.