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Pathway Description

Steroid Biosynthesis

Rattus norvegicus

Category:

Metabolite Pathway

Sub-Category:

Metabolic

Created: 2018-08-10

Last Updated: 2019-08-16

The steroid biosynthesis (or cholesterol biosynthesis) pathway is an anabolic metabolic pathway that produces steroids from simple precursors. It starts with the mevalonate pathway, where acetyl-CoA and acetoacetyl-CoA are the first two building blocks. These compounds are joined together via the enzyme hydroxy-3-methylgutaryl (HMG)-CoA synthase to produce the compound known as hydroxy-3-methylgutaryl-CoA (HMG-CoA). This compound is then reduced to mevalonic acid via the enzyme HMG-CoA reductase. It is important to note that HMG-CoA reductase is the protein target of many cholesterol-lowering drugs called statins (PMID: 12602122). The resulting mevalonic acid (or mevalonate) is then phosphorylated by the enzyme known as mevalonate kinase to form mevalonate-5-phosphate, which is then phosphorylated again by phosphomevalonate kinase to form mevolonate-5-pyrophsophate. This pyrophosphorylated compound is subsequently decarboxylated via the enzyme mevolonate-5-pyrophsophate decarboxylase to form isopentylpyrophosphate (IPP). IPP can also be isomerized (via isopentenyl-PP-isomerase) to form dimethylallylpyrophosphate (DMAPP). IPP and DMAPP can both donate isoprene units, which can then be joined together to make farnesyl and geranylgeranyl intermediates. Specifically, three molecules of IPP condense to form farnesyl pyrophosphate through the action of the enzyme known as geranyl transferase. Two molecules of farnesyl pyrophosphate then condense to form a molecule known as squalene by the action of the enzyme known as squalene synthase in the cell’s endoplasmic reticulum. The enzyme oxidosqualene cyclase then cyclizes squalene to form lanosterol. Lanosterol is a tetracyclic triterpenoid, and serves as the framework from which all steroids are derived. 14-Demethylation of lanosterol by a cytochrome P450 enzyme known as CYP51 eventually yields cholesterol. Cholesterol is the central steroid in human biology. It can be obtained from animal fats consumed in the diet or synthesized de novo (as described above). Cholesterol is an essential constituent of lipid bilayer membranes (where it forms cholesterol esters) and is the starting point for the biosynthesis of steroid hormones, bile acids and bile salts, and vitamin D. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (via glucocorticoids such as cortisol), salt balance (mineralocorticoids such as aldosterone), and sexual development and function (via androgens such as testosterone and estrogens such as estradiol). Bile acids and bile salts (such as taurocholate) are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Cholesterol is the main constituent of atheromas. These are the fatty lumps found in the walls of arteries that occur in atherosclerosis and, when ruptured, can cause heart attacks.

References

Steroid Biosynthesis References

Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.

Pubmed: 15489334

Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR: Mevalonate kinase is a cytosolic enzyme in humans. J Cell Sci. 2004 Feb 1;117(Pt 4):631-9. doi: 10.1242/jcs.00910.

Pubmed: 14730012

Stamellos KD, Shackelford JE, Tanaka RD, Krisans SK: Mevalonate kinase is localized in rat liver peroxisomes. J Biol Chem. 1992 Mar 15;267(8):5560-8.

Pubmed: 1312092

Tanaka RD, Lee LY, Schafer BL, Kratunis VJ, Mohler WA, Robinson GW, Mosley ST: Molecular cloning of mevalonate kinase and regulation of its mRNA levels in rat liver. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2872-6. doi: 10.1073/pnas.87.8.2872.

Pubmed: 2158094

Gibbs RA, Weinstock GM, Metzker ML, Muzny DM, Sodergren EJ, Scherer S, Scott G, Steffen D, Worley KC, Burch PE, Okwuonu G, Hines S, Lewis L, DeRamo C, Delgado O, Dugan-Rocha S, Miner G, Morgan M, Hawes A, Gill R, Celera, Holt RA, Adams MD, Amanatides PG, Baden-Tillson H, Barnstead M, Chin S, Evans CA, Ferriera S, Fosler C, Glodek A, Gu Z, Jennings D, Kraft CL, Nguyen T, Pfannkoch CM, Sitter C, Sutton GG, Venter JC, Woodage T, Smith D, Lee HM, Gustafson E, Cahill P, Kana A, Doucette-Stamm L, Weinstock K, Fechtel K, Weiss RB, Dunn DM, Green ED, Blakesley RW, Bouffard GG, De Jong PJ, Osoegawa K, Zhu B, Marra M, Schein J, Bosdet I, Fjell C, Jones S, Krzywinski M, Mathewson C, Siddiqui A, Wye N, McPherson J, Zhao S, Fraser CM, Shetty J, Shatsman S, Geer K, Chen Y, Abramzon S, Nierman WC, Havlak PH, Chen R, Durbin KJ, Egan A, Ren Y, Song XZ, Li B, Liu Y, Qin X, Cawley S, Worley KC, Cooney AJ, D'Souza LM, Martin K, Wu JQ, Gonzalez-Garay ML, Jackson AR, Kalafus KJ, McLeod MP, Milosavljevic A, Virk D, Volkov A, Wheeler DA, Zhang Z, Bailey JA, Eichler EE, Tuzun E, Birney E, Mongin E, Ureta-Vidal A, Woodwark C, Zdobnov E, Bork P, Suyama M, Torrents D, Alexandersson M, Trask BJ, Young JM, Huang H, Wang H, Xing H, Daniels S, Gietzen D, Schmidt J, Stevens K, Vitt U, Wingrove J, Camara F, Mar Alba M, Abril JF, Guigo R, Smit A, Dubchak I, Rubin EM, Couronne O, Poliakov A, Hubner N, Ganten D, Goesele C, Hummel O, Kreitler T, Lee YA, Monti J, Schulz H, Zimdahl H, Himmelbauer H, Lehrach H, Jacob HJ, Bromberg S, Gullings-Handley J, Jensen-Seaman MI, Kwitek AE, Lazar J, Pasko D, Tonellato PJ, Twigger S, Ponting CP, Duarte JM, Rice S, Goodstadt L, Beatson SA, Emes RD, Winter EE, Webber C, Brandt P, Nyakatura G, Adetobi M, Chiaromonte F, Elnitski L, Eswara P, Hardison RC, Hou M, Kolbe D, Makova K, Miller W, Nekrutenko A, Riemer C, Schwartz S, Taylor J, Yang S, Zhang Y, Lindpaintner K, Andrews TD, Caccamo M, Clamp M, Clarke L, Curwen V, Durbin R, Eyras E, Searle SM, Cooper GM, Batzoglou S, Brudno M, Sidow A, Stone EA, Venter JC, Payseur BA, Bourque G, Lopez-Otin C, Puente XS, Chakrabarti K, Chatterji S, Dewey C, Pachter L, Bray N, Yap VB, Caspi A, Tesler G, Pevzner PA, Haussler D, Roskin KM, Baertsch R, Clawson H, Furey TS, Hinrichs AS, Karolchik D, Kent WJ, Rosenbloom KR, Trumbower H, Weirauch M, Cooper DN, Stenson PD, Ma B, Brent M, Arumugam M, Shteynberg D, Copley RR, Taylor MS, Riethman H, Mudunuri U, Peterson J, Guyer M, Felsenfeld A, Old S, Mockrin S, Collins F: Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004 Apr 1;428(6982):493-521. doi: 10.1038/nature02426.

Pubmed: 15057822

Florea L, Di Francesco V, Miller J, Turner R, Yao A, Harris M, Walenz B, Mobarry C, Merkulov GV, Charlab R, Dew I, Deng Z, Istrail S, Li P, Sutton G: Gene and alternative splicing annotation with AIR. Genome Res. 2005 Jan;15(1):54-66. doi: 10.1101/gr.2889405.

Pubmed: 15632090

Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, Olsen JV: Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun. 2012 Jun 6;3:876. doi: 10.1038/ncomms1871.

Pubmed: 22673903

Paton VG, Shackelford JE, Krisans SK: Cloning and subcellular localization of hamster and rat isopentenyl diphosphate dimethylallyl diphosphate isomerase. A PTS1 motif targets the enzyme to peroxisomes. J Biol Chem. 1997 Jul 25;272(30):18945-50. doi: 10.1074/jbc.272.30.18945.

Pubmed: 9228075

Clarke CF, Tanaka RD, Svenson K, Wamsley M, Fogelman AM, Edwards PA: Molecular cloning and sequence of a cholesterol-repressible enzyme related to prenyltransferase in the isoprene biosynthetic pathway. Mol Cell Biol. 1987 Sep;7(9):3138-46. doi: 10.1128/mcb.7.9.3138.

Pubmed: 3670308

Teruya JH, Kutsunai SY, Spear DH, Edwards PA, Clarke CF: Testis-specific transcription initiation sites of rat farnesyl pyrophosphate synthetase mRNA. Mol Cell Biol. 1990 May;10(5):2315-26. doi: 10.1128/mcb.10.5.2315.

Pubmed: 2325654

Matsumura Y, Kuzuguchi T, Sagami H: Relationship between intron 4b splicing of the rat geranylgeranyl diphosphate synthase gene and the active enzyme expression level. J Biochem. 2004 Sep;136(3):301-12. doi: 10.1093/jb/mvh130.

Pubmed: 15598886

Shechter I, Klinger E, Rucker ML, Engstrom RG, Spirito JA, Islam MA, Boettcher BR, Weinstein DB: Solubilization, purification, and characterization of a truncated form of rat hepatic squalene synthetase. J Biol Chem. 1992 Apr 25;267(12):8628-35.

Pubmed: 1569107

McKenzie TL, Jiang G, Straubhaar JR, Conrad DG, Shechter I: Molecular cloning, expression, and characterization of the cDNA for the rat hepatic squalene synthase. J Biol Chem. 1992 Oct 25;267(30):21368-74.

Pubmed: 1400448

Sakakibara J, Watanabe R, Kanai Y, Ono T: Molecular cloning and expression of rat squalene epoxidase. J Biol Chem. 1995 Jan 6;270(1):17-20. doi: 10.1074/jbc.270.1.17.

Pubmed: 7814369

Abe I, Abe T, Lou W, Masuoka T, Noguchi H: Site-directed mutagenesis of conserved aromatic residues in rat squalene epoxidase. Biochem Biophys Res Commun. 2007 Jan 5;352(1):259-63. doi: 10.1016/j.bbrc.2006.11.014. Epub 2006 Nov 13.

Pubmed: 17112472

This pathway was propagated using PathWhiz - Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.

Propagated from SMP0000023

Highlighted elements will appear in red.

Highlight Compounds

	(R)-5-Diphosphomevalonic acid
	(S)-2,3-Epoxysqualene
	24,25-Dihydrolanosterol
	3-Hydroxy-3-methylglutaryl-CoA
	3-Keto-4-methylzymosterol
	4,4-Dimethyl-5a-cholesta-8,24-dien-3-b-ol
	4,4-Dimethyl-5a-cholesta-8-en-3b-ol
	4,4-Dimethylcholesta-8,14,24-trienol
	4a-Methylzymosterol
	4a-Methylzymosterol-4-carboxylic acid
	5a-Cholest-8-en-3b-ol
	5a-Cholesta-7,24-dien-3b-ol
	7-Dehydrocholesterol
	7-Dehydrodesmosterol
	8-Dehydrocholesterol
	Acetoacetyl-CoA
	Acetyl-CoA
	Adenosine diphosphate
	Adenosine triphosphate
	Carbon dioxide
	Cholesterol
	Cholesterol Ester
	Coenzyme A
	Desmosterol
	Dimethylallylpyrophosphate
	FAD
	Farnesyl pyrophosphate
	Fatty acid
	Formic acid
	Geranyl-PP
	Heme
	Iron
	Isopentenyl pyrophosphate
	Lanosterol
	Lathosterol
	Magnesium
	Mevalonic acid
	Mevalonic acid-5P
	NADP
	NADPH
	Oxygen
	Phosphate
	Pyrophosphate
	Squalene
	Vitamin D3
	Water
	Zymosterol intermediate 2

Highlight Proteins

	3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
	3-hydroxy-3-methylglutaryl-coenzyme A reductase
	3-keto-steroid reductase
	Acetyl-CoA acetyltransferase, cytosolic
	Delta(24)-sterol reductase
	Diphosphomevalonate decarboxylase
	Farnesyl pyrophosphate synthase
	Geranylgeranyl pyrophosphate synthase
	Isopentenyl-diphosphate Delta-isomerase 1
	Lamin-B receptor
	Lanosterol 14-alpha demethylase
	Lanosterol synthase
	Lathosterol oxidase
	Lysosomal acid lipase/cholesteryl ester hydrolase
	Methylsterol monooxygenase 1
	Mevalonate kinase
	Phosphomevalonate kinase
	Squalene monooxygenase
	Squalene synthase
	Sterol O-acyltransferase 1
	Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating

Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.

Visualize Compound Data

		(R)-5-Diphosphomevalonic acid
		(S)-2,3-Epoxysqualene
		24,25-Dihydrolanosterol
		3-Hydroxy-3-methylglutaryl-CoA
		3-Keto-4-methylzymosterol
		4,4-Dimethyl-5a-cholesta-8,24-dien-3-b-ol
		4,4-Dimethyl-5a-cholesta-8-en-3b-ol
		4,4-Dimethylcholesta-8,14,24-trienol
		4a-Methylzymosterol
		4a-Methylzymosterol-4-carboxylic acid
		5a-Cholest-8-en-3b-ol
		5a-Cholesta-7,24-dien-3b-ol
		7-Dehydrocholesterol
		7-Dehydrodesmosterol
		8-Dehydrocholesterol
		Acetoacetyl-CoA
		Acetyl-CoA
		Adenosine diphosphate
		Adenosine triphosphate
		Carbon dioxide
		Cholesterol
		Cholesterol Ester
		Coenzyme A
		Desmosterol
		Dimethylallylpyrophosphate
		FAD
		Farnesyl pyrophosphate
		Fatty acid
		Formic acid
		Geranyl-PP
		Heme
		Iron
		Isopentenyl pyrophosphate
		Lanosterol
		Lathosterol
		Magnesium
		Mevalonic acid
		Mevalonic acid-5P
		NADP
		NADPH
		Oxygen
		Phosphate
		Pyrophosphate
		Squalene
		Vitamin D3
		Water
		Zymosterol intermediate 2

Visualize Protein Data

		3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
		3-hydroxy-3-methylglutaryl-coenzyme A reductase
		3-keto-steroid reductase
		Acetyl-CoA acetyltransferase, cytosolic
		Delta(24)-sterol reductase
		Diphosphomevalonate decarboxylase
		Farnesyl pyrophosphate synthase
		Geranylgeranyl pyrophosphate synthase
		Isopentenyl-diphosphate Delta-isomerase 1
		Lamin-B receptor
		Lanosterol 14-alpha demethylase
		Lanosterol synthase
		Lathosterol oxidase
		Lysosomal acid lipase/cholesteryl ester hydrolase
		Methylsterol monooxygenase 1
		Mevalonate kinase
		Phosphomevalonate kinase
		Squalene monooxygenase
		Squalene synthase
		Sterol O-acyltransferase 1
		Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating

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