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MetaCyc Pathway: cholesterol biosynthesis I

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:
Cholesterol is an important structural component of eukaryotic cell membranes. It is also a precursor of steroid hormones and bile acids. The impact of cholesterol and its regulation on human health is well known. Its role in arteriosclerosis, and drug therapy for this process, has been extensively studied (reviewed in [Knopp99]). Nobel prizes in Physiology or Medicine were awarded to Konrad Bloch in 1963 and to M. S. Brown and J. L. Goldstein in 1985 for their work on the metabolism and regulation of cholesterol. Several interesting historical reviews detail the discovery of cholesterol and work leading to the elucidation of its structure and function [Bloch65, Bloch92, Vance00].

The first nine reactions of cholesterol biosynthesis are shown in the linked mevalonate pathway in HumanCyc. Mevalonate is the precursor of isoprenoids, which are involved in the biosynthesis of many classes of compounds in addition to cholesterol. As shown in the mevalonate pathway, the cholesterol molecule is formed from acetate units (reviewed in [Rilling85, Bloch65]). The acetate units are joined in a series of reactions to form farnesyl pyrophosphate, a branch point for the biosynthesis of other isoprenoid compounds such as ubiquinone, dolichol, and farnesylated proteins. The mevalonate pathway is highly regulated, as reviewed in [Goldstein90]. HMG-CoA reductase from the mevalonate pathway is the rate-determining enzyme for the entire pathway from acetate to cholesterol. This enzyme is the target for the well-known cholesterol-lowering statin drugs (reviewed in [Knopp99]).

Farnesyl-diphosphate farnesyltransferase (squalene synthase) is the first specific enzyme in cholesterol biosynthesis. It catalyzes a 2-step reaction involving a "head-to-head" condensation of two molecules of farnesyl pyrophosphate to form presqualene pyrophosphate [Rilling69, Altman71, Corey76]. Presqualene pyrophosphate is then reduced to squalene. Details of the enzymatic reaction mechanism, which involves carbocation intermediates, have been described [Blagg02]. The importance of squalene synthase has been demonstrated in squalene synthase knockout mice, which results in embryonic lethality and retardation of development [Tozawa99]. Squalene epoxidase (monooxygenase) catalyzes oxygen-dependent epoxidation of squalene [Yamamoto70]. Oxidosqualene cyclase (lanosterol synthase) catalyzes its remarkable cyclization, in a single reaction, to form lanosterol [Dean67]. This cyclization mechanism was proposed by several researchers, but the correct structure was determined by R. B. Woodward and K. Bloch [Woodward53], and reviewed in [Bloch65].

The enzymology of the multistep conversion of lanosterol to cholesterol was largely determined in rat liver by J. L. Gaylor and coworkers (reviewed in [Gaylor02]). The human pathway is therefore inferred from this work. The order of some of the reactions in this pathway may vary. The pathway shown here represents the reactions in a frequently published order, updated as follows. The last three reactions, as illustrated in two reviews ([Gaylor02, Rilling85]), have more recently been reordered as shown here ([Bae97], in [Waterham01], and reviewed in [Gaylor02]). Previously, the isomerase reaction was followed by the Δ5-desaturase, the Δ7-reductase (producing desmosterol) and the Δ24-reductase, producing cholesterol (as shown by clicking on the pathway link above that leads to pathway cholesterol biosynthesis III (via desmosterol)) (reviewed in [Gaylor02, Rilling85], in [Salway04]). In the pathway shown here, the isomerase reaction is followed by the Δ24-reductase, the Δ5-desaturase and the Δ7-reductase, producing cholesterol. Desmosterol is not shown. This reordering is based on substrate specificity studies of the Δ24 reductase [Bae97]. However, the Δ24 double bond reduction can also occur at other times, using other intermediates as substrates [Bae97]. This is evidenced by the genetic disorder desmosterolosis. In this disorder, patients have elevated levels of desmosterol in their plasma and tissues due to mutations in the Δ24-reductase gene [Waterham01]. Another route involves reduction of the Δ24 double bond at the point of lanosterol and leads to the production of 24,25-dihydrolanosterol. Metabolism of this compound is shown by clicking on the pathway link above that leads to pathway cholesterol biosynthesis II (via 24,25-dihydrolanosterol).

The lanosterol-to-cholesterol conversion involves the oxidative removal of three methyl groups, reduction of double bonds, and migration of the lanosterol double bond to a new position in cholesterol (in [Kawata85] and reviewed in [Gaylor02]). Unlike the mostly cytosolic reactions of the mevalonate pathway, the reactions shown here are catalyzed by membrane-bound enzymes (reviewed in [Gaylor02, Rilling85]). In rat liver, they have been localized in the endoplasmic reticulum [Reinhart87]. Solubilization and characterization of these enzymes had to be achieved before this segment of the pathway could be determined, as reviewed in [Gaylor02]. Human genes have been identified for all the enzymes in this pathway and human disorders of cholesterol metabolism have been associated with genetic defects in most of these enzymes. Mouse models also exist for several of these human disorders ([Marijanovic03] and reviewed in [Herman03]).

In the pathway shown here, the first of the three methyl groups, the 14α methyl group, is removed from lanosterol by a cytochrome P450 isozyme [Trzaskos84]. The reaction proceeds through alcohol and aldehyde intermediates [Shafiee86]. This is followed by decarbonylation with formate release, and Δ14 double bond formation. Details of this reaction mechanism have been published and involve formation of a formyl ester intermediate (not shown), suggesting a Bayer-Villiger reaction mechanism ([Fischer91], and reviewed in [Gaylor02]). The resulting Δ14 double bond of the conjugated diene is then reduced by an NADPH-dependent reductase [Paik84].

Another multienzyme complex, C4 methyl sterol oxidase, removes the second (4α) and third (4β) methyl groups in a sequential oxidative series of reactions that include carboxylic acid intermediates [Miller70, Miller71a, Miller67, Miller70a]. This enzyme is not a cytochrome P450. It utilizes cytochrome b5 as an electron carrier [Kawata86, Fukushima81]. The first of the two decarboxylation reactions is accompanied by epimerization of the 4β methyl group to the 4α position [Rahimtula72]. Thus, after subsequent reduction, the remaining methyl group is in the 4α orientation for further stereospecific oxidation by this enzyme ([Gaylor75, Sharpless68] and in reviews [Gaylor02, Rilling85, Schroepfer82]).

Following decarboxylation, a 3-ketosteroid intermediate is formed and is reduced by 3-ketosteroid reductase [Swindell68, Billheimer81]. The final demethylated intermediate then undergoes isomerization of the Δ8(9) double bond, which moves to the Δ7(8) position of the sterol B-ring [Bechtold72, Paik86]. The Δ24-reductase then catalyzes reduction of the side chain double bond [Bae97]. The Δ5-desaturase is a multienzyme system utilizing cytochrome b5 as an electron carrier. It catalyzes formation of the Δ5 double bond to form 7-dehydro-cholesterol ([Kawata86, Kawata85], and in [Taton00]). The terminal enzyme of the pathway reduces the Δ7 double bond to form cholesterol [Lee97e].

Acknowledgment: We thank Drs. Anne Venturelli and Ripudaman Malhotra, SRI International, for their help in providing chemical names for many of the intermediates shown in this pathway.

Superpathways: superpathway of cholesterol biosynthesis

Subpathways: lanosterol biosynthesis , epoxysqualene biosynthesis


References

Altman71: Altman LJ, Kowerski RC, Rilling HC (1971). "Synthesis and conversion of presqualene alcohol to squalene." J. Amer. Chem. Soc. 1971 93:1782-3.

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

Bechtold72: Bechtold MM, Delwiche CV, Comal K, Gaylor JL (1972). "Investigation of the component reactions of oxidative sterol demethylation. Role of an endogenous microsomal source of reducing equivalents." J Biol Chem 247(23);7650-6. PMID: 4404598

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

Blagg02: Blagg BS, Jarstfer MB, Rogers DH, Poulter CD (2002). "Recombinant squalene synthase. A mechanism for the rearrangement of presqualene diphosphate to squalene." J Am Chem Soc 124(30);8846-53. PMID: 12137537

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

Corey76: Corey EJ, Volante RP (1976). "Application of unreactive analogs of terpenoid pyrophosphates to studies of multistep biosynthesis. Demonstration that "presqualene pyrophosphate" is an essential intermediate on the path to squalene." J. Amer. Chem. Soc. 1976 98:1291-3.

Dean67: Dean PD, Ortiz de Montellano PR, Bloch K, Corey EJ (1967). "A soluble 2,3-oxidosqualene sterol cyclase." J Biol Chem 242(12);3014-5. PMID: 6027261

Fischer91: Fischer RT, Trzaskos JM, Magolda RL, Ko SS, Brosz CS, Larsen B (1991). "Lanosterol 14 alpha-methyl demethylase. Isolation and characterization of the third metabolically generated oxidative demethylation intermediate." J Biol Chem 266(10);6124-32. PMID: 2007571

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

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

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

Goldstein90: Goldstein JL, Brown MS (1990). "Regulation of the mevalonate pathway." Nature 343(6257);425-30. PMID: 1967820

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

Kawata85: Kawata S, Trzaskos JM, Gaylor JL (1985). "Microsomal enzymes of cholesterol biosynthesis from lanosterol. Purification and characterization of delta 7-sterol 5-desaturase of rat liver microsomes." J Biol Chem 260(11);6609-17. PMID: 3997841

Kawata86: Kawata S, Trzaskos JM, Gaylor JL (1986). "Affinity chromatography of microsomal enzymes on immobilized detergent-solubilized cytochrome b5." J Biol Chem 261(8);3790-9. PMID: 3949790

Knopp99: Knopp RH (1999). "Drug treatment of lipid disorders." N Engl J Med 341(7);498-511. PMID: 10441607

Lee97e: Lee J-N, Paik Y-K (1997). "Cholesterol biosynthesis from lanosterol: development of a novel assay method, characterization, and solubilization of rat hepatic microsomal sterol Δ7-reductase." J. Biochem. Mol. Biol. 1997 30:370-377.

Marijanovic03: Marijanovic Z, Laubner D, Moller G, Gege C, Husen B, Adamski J, Breitling R (2003). "Closing the gap: identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis." Mol Endocrinol 17(9);1715-25. PMID: 12829805

Miller67: Miller WL, Kalafer ME, Gaylor JL, Delwiche CV (1967). "Investigation of the component reactions of oxidative sterol demethylation. Study of the aerobic and anaerobic processes." Biochemistry 6(9);2673-8. PMID: 4383278

Miller70: Miller WL, Gaylor JL (1970). "Investigation of the component reactions of oxidative sterol demethylation. Oxidation of a 4,4-dimethyl sterol to a 4 beta-methyl-4 alpha-carboxylic acid during cholesterol biosynthesis." J Biol Chem 245(20);5375-81. PMID: 4394229

Miller70a: Miller WL, Gaylor JL (1970). "Investigation of the component reactions of oxidative sterol demethylation. Oxidation of a 4 alpha-methyl sterol to a 4 alpha-carboxylic acid during cholesterol biosynthesis." J Biol Chem 245(20);5369-74. PMID: 4394228

Miller71a: Miller WL, Brady DR, Gaylor JL (1971). "Investigation of the component reactions of oxidative demethylation of sterols. Metabolism of 4 -hydroxymethyl steroids." J Biol Chem 246(16);5147-53. PMID: 4398294

Paik84: Paik YK, Trzaskos JM, Shafiee A, Gaylor JL (1984). "Microsomal enzymes of cholesterol biosynthesis from lanosterol. Characterization, solubilization, and partial purification of NADPH-dependent delta 8,14-steroid 14-reductase." J Biol Chem 259(21);13413-23. PMID: 6444198

Paik86: Paik YK, Billheimer JT, Magolda RL, Gaylor JL (1986). "Microsomal enzymes of cholesterol biosynthesis from lanosterol. Solubilization and purification of steroid 8-isomerase." J Biol Chem 261(14);6470-7. PMID: 2422166

Rahimtula72: Rahimtula AD, Gaylor JL (1972). "Partial purification of a microsomal sterol 4 -carboxylic acid decarboxylase." J Biol Chem 247(1);9-15. PMID: 4401584

Reinhart87: Reinhart MP, Billheimer JT, Faust JR, Gaylor JL (1987). "Subcellular localization of the enzymes of cholesterol biosynthesis and metabolism in rat liver." J Biol Chem 262(20);9649-55. PMID: 3597431

Rilling69: Rilling HC, Epstein WW (1969). "Studies on the mechanism of squalene biosynthesis. Presqualene, a pyrophosphorylated precursor to squalene." J. Amer. Chem. Soc. 1969 91:1041-2.

Rilling85: Rilling HC, Chayet LT "Biosynthesis of cholesterol." Sterols and Bile Acids, H. Danielsson and J. Sjovall (Eds.), 1985, Elsevier Science Publications, New York. pp. 1-39.

Salway04: Salway JG (2004). "Metabolism at a Glance." 3rd ed, Blackwell Publishing, Malden, MA, USA.

Schroepfer82: Schroepfer GJ (1982). "Sterol biosynthesis." Annu Rev Biochem 51;555-85. PMID: 6810750

Shafiee86: Shafiee A, Trzaskos JM, Paik YK, Gaylor JL (1986). "Oxidative demethylation of lanosterol in cholesterol biosynthesis: accumulation of sterol intermediates." J Lipid Res 27(1);1-10. PMID: 3514778

Sharpless68: Sharpless KB, Snyder TE, Spencer TA, Maheshwari KK, Guhn G, Clayton RB (1968). "Biological demethylation of 4,4-dimethyl sterols. Initial removal of the 4α-methyl group." J. Amer. Chem. Soc. 1968 90:6874-5.

Swindell68: Swindell AC, Gaylor JL (1968). "Investigation of the component reactions of oxidative sterol demethylation. Formation and metabolism of 3-ketosteroid intermediates." J Biol Chem 243(21);5546-55. PMID: 4387005

Taton00: Taton M, Husselstein T, Benveniste P, Rahier A (2000). "Role of highly conserved residues in the reaction catalyzed by recombinant Delta7-sterol-C5(6)-desaturase studied by site-directed mutagenesis." Biochemistry 39(4);701-11. PMID: 10651635

Tozawa99: Tozawa R, Ishibashi S, Osuga J, Yagyu H, Oka T, Chen Z, Ohashi K, Perrey S, Shionoiri F, Yahagi N, Harada K, Gotoda T, Yazaki Y, Yamada N (1999). "Embryonic lethality and defective neural tube closure in mice lacking squalene synthase." J Biol Chem 274(43);30843-8. PMID: 10521476

Trzaskos84: Trzaskos JM, Bowen WD, Shafiee A, Fischer RT, Gaylor JL (1984). "Cytochrome P-450-dependent oxidation of lanosterol in cholesterol biosynthesis. Microsomal electron transport and C-32 demethylation." J Biol Chem 259(21);13402-12. PMID: 6208195

Vance00: Vance DE, Van den Bosch H (2000). "Cholesterol in the year 2000." Biochim Biophys Acta 1529(1-3);1-8. PMID: 11111073

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

Woodward53: Woodward RB, Bloch k (1953). "The cyclization of squalene in cholesterol synthesis." J Am Chem Soc 75:2023-2024, 1953.

Yamamoto70: Yamamoto S, Bloch K (1970). "Studies on squalene epoxidase of rat liver." J Biol Chem 245(7);1670-4. PMID: 5438357

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

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

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

Filipovic87: Filipovic I, Buddecke E (1987). "Calmodulin antagonists suppress cholesterol synthesis by inhibiting sterol delta 24 reductase." Lipids 22(4);261-5. PMID: 3037232

Fischer89: Fischer RT, Stam SH, Johnson PR, Ko SS, Magolda RL, Gaylor JL, Trzaskos JM (1989). "Mechanistic studies of lanosterol 14 alpha-methyl demethylase: substrate requirements for the component reactions catalyzed by a single cytochrome P-450 isozyme." J Lipid Res 30(10);1621-32. PMID: 2614264

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

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

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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

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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
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