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MetaCyc Pathway: bile acid biosynthesis, neutral pathway
Inferred from experimentTraceable author statement to experimental support

Pathway diagram: bile acid biosynthesis, neutral pathway

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: bile acid biosynthesis (classic pathway)

Superclasses: BiosynthesisFatty Acid and Lipid BiosynthesisSterol Biosynthesis

Some taxa known to possess this pathway include : Homo sapiens, Mus musculus, Oryctolagus cuniculus, Rattus norvegicus

Expected Taxonomic Range: Vertebrata

General Background

The biosynthesis of bile acids is a major route of cholesterol catabolism. It converts the hydrophobic, insoluble cholesterol molecule into soluble bile acids. Accumulation of excess cholesterol has been shown to be a risk factor for several diseases, notably atherosclerosis. Expression of the enzymes involved in bile acid biosynthesis is highly regulated by transcription factors to ensure their availability during changing metabolic conditions. Inherited mutations in some of these enzymes result in a variety of severe metabolic disorders.

The structures of bile acids vary, as do their proportions in different species. In the liver, the primary bile acids are conjugated with glycine or taurine before secretion into the bile. Further conversion into secondary bile acids such as deoxycholate, or lithocholate occurs through the action of microbial enzymes in the gut.

Four pathways for bile acid biosynthesis have been described. The neutral (classic) pathway begins with hydroxylation at the 7α ring position of cholesterol (EC The acidic (alternate) pathway begins with 27-hydroxylation of the cholesterol side chain (EC The 24-hydroxylase (EC and 25-hydroxylase EC pathways begin with these respective side chain hydroxylations. The three side chain hydroxylations are followed by 7α hydroxylation (via EC or EC Hydroxylation at the 7α position is a characteristic of bile acids. All but one of these reactions are catalyzed by enzymes of the cytochrome P450 family.

The acidic, 24-hydroxylase and 25-hydroxylase pathways have only been partly illustrated in the literature (later reaction steps were omitted). It should also be noted that the exact order of reactions in all of the bile acid biosynthetic pathways remains unclear because many of the intermediates are substrates for more than one biosynthetic enzyme. In addition, the relative contributions of the different pathways may vary by species, age and physiological condition (in [Norlin07]). The neutral pathway is considered the quantitatively most important pathway in humans. The acidic pathway leads mainly to chenodeoxycholate and may be more important in rats. The 24- and 25-hydroxylase pathways are considered minor pathways. Reviewed extensively in [Russell03, Norlin07, Russell08, Javitt02].

About This Pathway

This pathway shows the neutral (classic) pathway for the biosynthesis of two possible bile acid conjugates of cholate and chenodeoxycholate. It is represented here essentially as shown in [Russell03] and as shown in part in [Norlin07] and [Ferdinandusse05]. The pathway is initiated by hydroxylation at the 7α position of the cholesterol ring structure, followed by reactions that further modify the cholesterol rings, oxidize and shorten the side chain, and conjugate the bile acid with an amino acid to increase solubility. Free cholate may result from regulated action of peroxisomal coenzyme A thioesterase 2 on choloyl-CoA, although the biological consequences of changes in the ratio of free and conjugated forms are not understood. More than 98% of bile acids excreted from the liver are conjugated (in [Russell03]). Humans and rats produce both glycocholate and taurocholate. Mice produce taurocholate due to difference in substrate specificity of their conjugating enzyme ( [Falany97, Hunt02] and reviewed in [Russell03]).

The enzymes in the pathway are found in multiple subcellular locations including the endoplasmic reticulum, cytosol, mitochondrion and peroxisome (as indicated on the enzyme display pages). These enzymes also function in steroid metabolism, very long chain fatty acid metabolism and vitamin D biosynthesis. Reviewed in [Russell03, Norlin07, Russell08, Javitt02]. Oxysterols produced during bile acid biosynthesis also function in cholesterol homeostasis (reviewed in [Norlin07].

A branch point after the second reaction at 7α-hydroxycholest-4-en-3-one leads to a similar biosynthesis of chenodeoxycholate derivatives in most mammalian species. This branch lacks the 7α-hydroxycholest-4-en-3-one 12α-hydroxylase step (as illustrated in [Russell03, Norlin07]). Cholate differs from chenodeoxycholate by the presence of a hydroxyl group at the 12α position. The relevant enzymes in the pathway shown here are also active on the corresponding dihydroxy substrates that lead to chenodeoxycholate derivatives [Okuda84, Usui86, Okuda88, Wheeler97, Schmitz97, Hunt08, Kurosawa01, Bunya98, Killenberg78, Prydz86]. Other bile acids (and their derivatives) such as muricholate, ursodeoxycholate and hyodeoxycholate are also produced by mouse, bear and pig, respectively (in [Russell03]).

Unification Links: KEGG:map00120, Reactome:REACT_11041

Created 03-Oct-2008 by Fulcher CA, SRI International


Bunya98: Bun-ya M, Maebuchi M, Kamiryo T, Kurosawa T, Sato M, Tohma M, Jiang LL, Hashimoto T (1998). "Thiolase involved in bile acid formation." J Biochem 123(2);347-52. PMID: 9538213

Cuebas02: Cuebas DA, Phillips C, Schmitz W, Conzelmann E, Novikov DK (2002). "The role of alpha-methylacyl-CoA racemase in bile acid synthesis." Biochem J 363(Pt 3);801-7. PMID: 11964182

Falany97: Falany CN, Fortinberry H, Leiter EH, Barnes S (1997). "Cloning, expression, and chromosomal localization of mouse liver bile acid CoA:amino acid N-acyltransferase." J Lipid Res 38(6);1139-48. PMID: 9215542

Ferdinandusse05: Ferdinandusse S, Denis S, Overmars H, Van Eeckhoudt L, Van Veldhoven PP, Duran M, Wanders RJ, Baes M (2005). "Developmental changes of bile acid composition and conjugation in L- and D-bifunctional protein single and double knockout mice." J Biol Chem 280(19);18658-66. PMID: 15769750

Hunt02: Hunt MC, Solaas K, Kase BF, Alexson SE (2002). "Characterization of an acyl-coA thioesterase that functions as a major regulator of peroxisomal lipid metabolism." J Biol Chem 277(2);1128-38. PMID: 11673457

Hunt08: Hunt MC, Alexson SE (2008). "Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism." Prog Lipid Res 47(6);405-21. PMID: 18538142

Javitt02: Javitt NB (2002). "Cholesterol, hydroxycholesterols, and bile acids." Biochem Biophys Res Commun 292(5);1147-53. PMID: 11969205

Killenberg78: Killenberg PG, Jordan JT (1978). "Purification and characterization of bile acid-CoA:amino acid N-acyltransferase from rat liver." J Biol Chem 253(4);1005-10. PMID: 624713

Kurosawa01: Kurosawa T, Sato M, Nakano H, Fujiwara M, Murai T, Yoshimura T, Hashimoto T (2001). "Conjugation reactions catalyzed by bifunctional proteins related to beta-oxidation in bile acid biosynthesis." Steroids 66(2);107-14. PMID: 11146090

Norlin07: Norlin M, Wikvall K (2007). "Enzymes in the conversion of cholesterol into bile acids." Curr Mol Med 7(2);199-218. PMID: 17346171

Okuda84: Okuda A, Okuda K (1984). "Purification and characterization of delta 4-3-ketosteroid 5 beta-reductase." J Biol Chem 259(12);7519-24. PMID: 6736016

Okuda88: Okuda K, Masumoto O, Ohyama Y (1988). "Purification and characterization of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol 27-hydroxylase from female rat liver mitochondria." J Biol Chem 263(34);18138-42. PMID: 2848026

Prydz86: Prydz K, Kase BF, Bjorkhem I, Pedersen JI (1986). "Formation of chenodeoxycholic acid from 3 alpha, 7 alpha-dihydroxy-5 beta-cholestanoic acid by rat liver peroxisomes." J Lipid Res 27(6);622-8. PMID: 3746130

Russell03: Russell DW (2003). "The enzymes, regulation, and genetics of bile acid synthesis." Annu Rev Biochem 72;137-74. PMID: 12543708

Russell08: Russell DW (2008). "50 years of advances in bile acid synthesis and metabolism." J Lipid Res. PMID: 18815433

Schmitz97: Schmitz W, Helander HM, Hiltunen JK, Conzelmann E (1997). "Molecular cloning of cDNA species for rat and mouse liver alpha-methylacyl-CoA racemases." Biochem J 326 ( Pt 3);883-9. PMID: 9307041

Usui86: Usui E, Okuda K (1986). "Identification of 7 alpha,12 alpha-dihydroxy-5 beta-cholestan-3-one 3 alpha-hydroxysteroid dehydrogenase." Biochim Biophys Acta 877(1);158-66. PMID: 3459552

Wheeler97: Wheeler JB, Shaw DR, Barnes S (1997). "Purification and characterization of a rat liver bile acid coenzyme A ligase from rat liver microsomes." Arch Biochem Biophys 348(1);15-24. PMID: 9390170

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

Abrahamsson05: Abrahamsson A, Krapivner S, Gustafsson U, Muhrbeck O, Eggertsen G, Johansson I, Persson I, Angelin B, Ingelman-Sundberg M, Bjorkhem I, Einarsson C, van't Hooft FM (2005). "Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration." Atherosclerosis 182(1);37-45. PMID: 16115473

Amery00: Amery L, Fransen M, De Nys K, Mannaerts GP, Van Veldhoven PP (2000). "Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans." J Lipid Res 41(11);1752-9. PMID: 11060344

Andersson89: Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW (1989). "Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme." J Biol Chem 264(14);8222-9. PMID: 2722778

Andersson98: Andersson U, Eggertsen G, Bjorkhem I (1998). "Rabbit liver contains one major sterol 12alpha-hydroxylase with broad substrate specificity." Biochim Biophys Acta 1389(2);150-4. PMID: 9461256

Atsuta78: Atsuta Y, Okuda K (1978). "Isolation of rat liver mitochondrial ferredoxin and its reductase active in the 5beta-cholestane-3alpha, 7alpha, 12alpha-triol 26-hydroxylase." J Biol Chem 253(13);4653-8. PMID: 207706

Baumgart96: Baumgart E, Vanhooren JC, Fransen M, Mannaerts GP, Van Veldhoven PP (1996). "Mammalian peroxisomal acyl-CoA oxidases. III. Molecular characterization of human branched chain fatty acyl-CoA oxidase." Ann N Y Acad Sci 804;678-9. PMID: 8993592

Baumgart96a: Baumgart E, Vanhooren JC, Fransen M, Marynen P, Puype M, Vandekerckhove J, Leunissen JA, Fahimi HD, Mannaerts GP, van Veldhoven PP (1996). "Molecular characterization of the human peroxisomal branched-chain acyl-CoA oxidase: cDNA cloning, chromosomal assignment, tissue distribution, and evidence for the absence of the protein in Zellweger syndrome." Proc Natl Acad Sci U S A 93(24);13748-53. PMID: 8943006

Baumgart96b: Baumgart E, Vanhooren JC, Fransen M, Van Leuven F, Fahimi HD, Van Veldhoven PP, Mannaerts GP (1996). "Molecular cloning and further characterization of rat peroxisomal trihydroxycoprostanoyl-CoA oxidase." Biochem J 320 ( Pt 1);115-21. PMID: 8947475

Beigneux02: Beigneux A, Hofmann AF, Young SG (2002). "Human CYP7A1 deficiency: progress and enigmas." J Clin Invest 110(1);29-31. PMID: 12093884

Bennett96: Bennett MJ, Schlegel BP, Jez JM, Penning TM, Lewis M (1996). "Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+." Biochemistry 35(33);10702-11. PMID: 8718859

Bennett97: Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M (1997). "Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase." Structure 5(6);799-812. PMID: 9261071

Bhaumik07: Bhaumik P, Schmitz W, Hassinen A, Hiltunen JK, Conzelmann E, Wierenga RK (2007). "The catalysis of the 1,1-proton transfer by alpha-methyl-acyl-CoA racemase is coupled to a movement of the fatty acyl moiety over a hydrophobic, methionine-rich surface." J Mol Biol 367(4);1145-61. PMID: 17320106

Billheimer90: Billheimer JT, Strehl LL, Davis GL, Strauss JF, Davis LG (1990). "Characterization of a cDNA encoding rat sterol carrier protein2." DNA Cell Biol 9(3);159-65. PMID: 2340090

Bjorkhem02: Bjorkhem I, Araya Z, Rudling M, Angelin B, Einarsson C, Wikvall K (2002). "Differences in the regulation of the classical and the alternative pathway for bile acid synthesis in human liver. No coordinate regulation of CYP7A1 and CYP27A1." J Biol Chem 277(30);26804-7. PMID: 12011083

Black82: Black SD, Coon MJ (1982). "Structural features of liver microsomal NADPH-cytochrome P-450 reductase. Hydrophobic domain, hydrophilic domain, and connecting region." J Biol Chem 257(10);5929-38. PMID: 6802823

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

Breuer93: Breuer O, Sudjana-Sugiaman E, Eggertsen G, Chiang JY, Bjorkhem I (1993). "Cholesterol 7 alpha-hydroxylase is up-regulated by the competitive inhibitor 7-oxocholesterol in rat liver." Eur J Biochem 215(3);705-10. PMID: 8354276

Chen02a: Chen JY, Levy-Wilson B, Goodart S, Cooper AD (2002). "Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet." J Biol Chem 277(45);42588-95. PMID: 12202481

Chen09a: Chen W, Wu W, Zhao J, Yu C, Liu W, Jiang A, Zhang J (2009). "Molecular cloning and preliminary analysis of the human alpha-methylacyl-CoA racemase promoter." Mol Biol Rep 36(3);423-30. PMID: 18080842

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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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