Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of acetoacetyl CoA and the mitochondrial generation of (S)-3-hydroxy-3-methylglutaryl-CoA) are also associated with oxidation of fatty acids.

* Key recommended reading is highlighted with an asterisk

* Göbel A, Rauner M, Hofbauer LC, Rachner TD. (2020) Cholesterol and beyond - The role of the mevalonate pathway in cancer biology. Biochim Biophys Acta Rev Cancer, 1873 (2): 188351. [PMID:32007596]

* Juarez D, Fruman DA. (2021) Targeting the Mevalonate Pathway in Cancer. Trends Cancer, 7 (6): 525-540. [PMID:33358111]

Miziorko HM. (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys, 505 (2): 131-43. [PMID:20932952]

* Moutinho M, Nunes MJ, Rodrigues E. (2017) The mevalonate pathway in neurons: It's not just about cholesterol. Exp Cell Res, 360 (1): 55-60. [PMID:28232115]

* Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. (2016) The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer, 16 (11): 718-731. [PMID:27562463]

Ness GC. (2015) Physiological feedback regulation of cholesterol biosynthesis: Role of translational control of hepatic HMG-CoA reductase and possible involvement of oxylanosterols. Biochim Biophys Acta, 1851 (5): 667-73. [PMID:25701719]

Porter TD. (2015) Electron Transfer Pathways in Cholesterol Synthesis. Lipids, 50 (10): 927-36. [PMID:26344922]

* Proto MC, Fiore D, Piscopo C, Pagano C, Galgani M, Bruzzaniti S, Laezza C, Gazzerro P, Bifulco M. (2021) Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets. Prog Lipid Res, 82: 101099. [PMID:33915202]

Rozman D, Monostory K. (2010) Perspectives of the non-statin hypolipidemic agents. Pharmacol Ther, 127 (1): 19-40. [PMID:20420853]

Samaras K, Brodaty H, Sachdev PS. (2016) Does statin use cause memory decline in the elderly?. Trends Cardiovasc Med, 26 (6): 550-65. [PMID:27177529]

Seiki S, Frishman WH. (2009) Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev, 17 (2): 70-6. [PMID:19367148]

van der Burgh R, Ter Haar NM, Boes ML, Frenkel J. (2013) Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol, 147 (3): 197-206. [PMID:23110805]

Zhang H, Temel RE, Martel C. (2014) Cholesterol and lipoprotein metabolism: Early Career Committee contribution. Arterioscler Thromb Vasc Biol, 34 (9): 1791-4. [PMID:25142876]

1. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E et al.. (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA, 77 (7): 3957-61. [PMID:6933445]

2. Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G. (2000) Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys, 373 (1): 231-41. [PMID:10620343]

3. Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD. (1993) Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci USA, 90 (1): 80-4. [PMID:8419946]

4. Carbonell T, Freire E. (2005) Binding thermodynamics of statins to HMG-CoA reductase. Biochemistry, 44 (35): 11741-8. [PMID:16128575]

5. Dunford JE, Kwaasi AA, Rogers MJ, Barnett BL, Ebetino FH, Russell RG, Oppermann U, Kavanagh KL. (2008) Structure-activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. J Med Chem, 51 (7): 2187-95. [PMID:18327899]

6. Holdgate GA, Ward WH, McTaggart F. (2003) Molecular mechanism for inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase by rosuvastatin. Biochem Soc Trans, 31 (Pt 3): 528-31. [PMID:12773150]

7. Istvan ES, Deisenhofer J. (2001) Structural mechanism for statin inhibition of HMG-CoA reductase. Science, 292 (5519): 1160-4. [PMID:11349148]

8. Seiki S, Frishman WH. (2009) Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev, 17 (2): 70-6. [PMID:19367148]

9. Thilagavathi R, Kumar R, Aparna V, Sobhia ME, Gopalakrishnan B, Chakraborti AK. (2005) Three-dimensional quantitative structure (3-D QSAR) activity relationship studies on imidazolyl and N-pyrrolyl heptenoates as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitors by comparative molecular similarity indices analysis (CoMSIA). Bioorg Med Chem Lett, 15 (4): 1027-32. [PMID:15686906]

10. Thompson JF, Danley DE, Mazzalupo S, Milos PM, Lira ME, Harwood HJ. (1998) Truncation of human squalene synthase yields active, crystallizable protein. Arch Biochem Biophys, 350 (2): 283-90. [PMID:9473303]

Helen E. Benson (Past curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338 Hugh Robson Building George Square Edinburgh EH8 9XD UK