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Pathway Description
Steroid Biosynthesis
Bos taurus
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
Harhay GP, Sonstegard TS, Keele JW, Heaton MP, Clawson ML, Snelling WM, Wiedmann RT, Van Tassell CP, Smith TP: Characterization of 954 bovine full-CDS cDNA sequences. BMC Genomics. 2005 Nov 23;6:166. doi: 10.1186/1471-2164-6-166.
Pubmed: 16305752
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Pubmed: 19390049
Lefebvre L, Vanderplasschen A, Ciminale V, Heremans H, Dangoisse O, Jauniaux JC, Toussaint JF, Zelnik V, Burny A, Kettmann R, Willems L: Oncoviral bovine leukemia virus G4 and human T-cell leukemia virus type 1 p13(II) accessory proteins interact with farnesyl pyrophosphate synthetase. J Virol. 2002 Feb;76(3):1400-14. doi: 10.1128/jvi.76.3.1400-1414.2002.
Pubmed: 11773414
Kuzuguchi T, Morita Y, Sagami I, Sagami H, Ogura K: Human geranylgeranyl diphosphate synthase. cDNA cloning and expression. J Biol Chem. 1999 Feb 26;274(9):5888-94. doi: 10.1074/jbc.274.9.5888.
Pubmed: 10026212
Sonstegard TS, Capuco AV, White J, Van Tassell CP, Connor EE, Cho J, Sultana R, Shade L, Wray JE, Wells KD, Quackenbush J: Analysis of bovine mammary gland EST and functional annotation of the Bos taurus gene index. Mamm Genome. 2002 Jul;13(7):373-9. doi: 10.1007/s00335-001-2145-4.
Pubmed: 12140684
Zimin AV, Delcher AL, Florea L, Kelley DR, Schatz MC, Puiu D, Hanrahan F, Pertea G, Van Tassell CP, Sonstegard TS, Marcais G, Roberts M, Subramanian P, Yorke JA, Salzberg SL: A whole-genome assembly of the domestic cow, Bos taurus. Genome Biol. 2009;10(4):R42. doi: 10.1186/gb-2009-10-4-r42. Epub 2009 Apr 24.
Pubmed: 19393038
Wu TK, Huang CY, Ko CY, Chang CH, Chen YJ, Liao HK: Purification, tandem mass characterization, and inhibition studies of oxidosqualene-lanosterol cyclase enzyme from bovine liver. Arch Biochem Biophys. 2004 Jan 1;421(1):42-53. doi: 10.1016/j.abb.2003.09.036.
Pubmed: 14678783
Rozman D, Seliskar M, Cotman M, Fink M: Pre-cholesterol precursors in gametogenesis. Mol Cell Endocrinol. 2005 Apr 29;234(1-2):47-56. doi: 10.1016/j.mce.2004.11.009.
Pubmed: 15836952
Wang F, Shen Y, Song X, Xia G, Chen X, Zhou B, Lei L: cDNA cloning, genomic structure and expression analysis of the bovine lanosterol 14alpha-demethylase (CYP51) in gonads. Biol Pharm Bull. 2006 Mar;29(3):430-6. doi: 10.1248/bpb.29.430.
Pubmed: 16508140
Bennati AM, Castelli M, Della Fazia MA, Beccari T, Caruso D, Servillo G, Roberti R: Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol Delta14-reductase in human cholesterol biosynthesis. Biochim Biophys Acta. 2006 Jul;1761(7):677-85. doi: 10.1016/j.bbalip.2006.05.004. Epub 2006 May 19.
Pubmed: 16784888
Roberti R, Bennati AM, Galli G, Caruso D, Maras B, Aisa C, Beccari T, Della Fazia MA, Servillo G: Cloning and expression of sterol Delta 14-reductase from bovine liver. Eur J Biochem. 2002 Jan;269(1):283-90. doi: 10.1046/j.0014-2956.2001.02646.x.
Pubmed: 11784322
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
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