Squalene monooxygenase explained

Squalene epoxidase
Ec Number:	1.14.13.132
Cas Number:	9029-62-3
Go Code:	0004506
Width:	292px

Squalene monooxygenase (also called squalene epoxidase) is a eukaryotic enzyme that uses NADPH and diatomic oxygen to oxidize squalene to 2,3-oxidosqualene (squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway.^[1] In humans, squalene epoxidase is encoded by the SQLE gene.^[2] Several eukaryote genomes lack a squalene monooxygenase encoding gene, but instead encode an alternative squalene epoxidase that performs the same task.^[3]

Mechanism

The canonical squalene monooxygenase is a flavoprotein monooxygenase. Flavoprotein monooxygenase form flavin hydroperoxides at the enzyme active site, which then transfer the terminal oxygen atom of the hydroperoxide to the substrate. Squalene monooxygenase differs from other flavin monooxygenases in that the oxygen is inserted into the substrate as an epoxide rather than as a hydroxyl group. This enzyme contains a loosely bound FAD flavin and obtains electrons from NADPH-cytochrome P450 reductase, rather than binding NADPH directly. The alternative squalene epoxidase belongs to the fatty acid hydroxylase superfamily and obtains electrons from cytochrome b5.^[3]

Inhibitors

Inhibitors of squalene epoxidase have found application mainly as antifungal drugs:^[4]

• butenafine
• naftifine
• terbinafine^[5]

Since squalene epoxidase is on the biosynthetic pathway leading to production of cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.^[6]

Localization

In baker's yeast (Saccharomyces cerevisiae), squalene epoxidase is localized to both the endoplasmic reticulum and lipid droplets. Only the ER localized protein is active.

Additional products

Squalene epoxidase also catalyzes the formation of diepoxysqualene (DOS). DOS is converted to 24(S),25-epoxylanosterol by lanosterol synthase.

See also

• Antifungal drug#Allylamines

Further reading

• Ma J, Dempsey AA, Stamatiou D, Marshall KW, Liew CC . Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects . Atherosclerosis . 191 . 1 . 63–72 . Mar 2007 . 16806233 . 10.1016/j.atherosclerosis.2006.05.032 .
• Laden BP, Tang Y, Porter TD . Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase . Archives of Biochemistry and Biophysics . 374 . 2 . 381–8 . Feb 2000 . 10666321 . 10.1006/abbi.1999.1629 .
• Helms MW, Kemming D, Pospisil H, Vogt U, Buerger H, Korsching E, Liedtke C, Schlotter CM, Wang A, Chan SY, Brandt BH . Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease . British Journal of Cancer . 99 . 5 . 774–80 . Sep 2008 . 18728668 . 2528137 . 10.1038/sj.bjc.6604556 .
• Nagai M, Sakakibara J, Nakamura Y, Gejyo F, Ono T . SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase . Biochemical and Biophysical Research Communications . 295 . 1 . 74–80 . Jul 2002 . 12083769 . 10.1016/S0006-291X(02)00623-X .
• Liu Y, Sun W, Zhang K, Zheng H, Ma Y, Lin D, Zhang X, Feng L, Lei W, Zhang Z, Guo S, Han N, Tong W, Feng X, Gao Y, Cheng S . Identification of genes differentially expressed in human primary lung squamous cell carcinoma . Lung Cancer . 56 . 3 . 307–17 . Jun 2007 . 17316888 . 10.1016/j.lungcan.2007.01.016 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Lu Y, Dollé ME, Imholz S, van 't Slot R, Verschuren WM, Wijmenga C, Feskens EJ, Boer JM . Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations . Journal of Lipid Research . 49 . 12 . 2582–9 . Dec 2008 . 18660489 . 10.1194/jlr.M800232-JLR200 . free .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415-8 . Jan 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . Nov 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Nakamura Y, Sakakibara J, Izumi T, Shibata A, Ono T . Transcriptional regulation of squalene epoxidase by sterols and inhibitors in HeLa cells . The Journal of Biological Chemistry . 271 . 14 . 8053–6 . Apr 1996 . 8626488 . 10.1074/jbc.271.14.8053 . free .
• Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T . Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1 . Genomics . 44 . 1 . 141–3 . Aug 1997 . 9286711 . 10.1006/geno.1997.4825 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . Oct 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .

Notes and References

1. Web site: Entrez Gene: SQLE squalene epoxidase .
2. Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T . Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1 . Genomics . 44 . 1 . 141–3 . Aug 1997 . 9286711 . 10.1006/geno.1997.4825 .
3. Pollier J, Vancaester E, Kuzhiumparambil U, Vickers CE, Vandepoele K, Goossens A, Fabris M . A widespread alternative squalene epoxidase participates in eukaryote steroid biosynthesis . Nature Microbiology . 4 . 2 . 226–233 . 30478288 . 10.1038/s41564-018-0305-5 . 2019 . 1854/LU-8587985 . 53726187 . free .
4. Favre B, Ryder NS . Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents . Antimicrobial Agents and Chemotherapy . 40 . 2 . 443–7 . Feb 1996 . 8834895 . 163131 . 10.1128/AAC.40.2.443.
5. Ryder NS . Terbinafine: mode of action and properties of the squalene epoxidase inhibition . The British Journal of Dermatology . 126 . 2–7 . Feb 1992 . Suppl 39 . 1543672 . 10.1111/j.1365-2133.1992.tb00001.x . 19780957 .
6. Chugh A, Ray A, Gupta JB . Squalene epoxidase as hypocholesterolemic drug target revisited . Progress in Lipid Research . 42 . 1 . 37–50 . Jan 2003 . 12467639 . 10.1016/S0163-7827(02)00029-2 .