Squalene monooxygenase
Squalene monooxygenase is an enzyme that uses NADPH and molecular 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] Note that SqMO is NOT the same as SqE.
Mechanism
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 as an epoxide rather than as a hydroxyl group. Squalene monooxygenase contains a loosely bound FAD flavin and obtains electrons from NADPH-cytochrome P450 reductase, rather than binding the nicotinamide cofactor NADPH directly.
Inhibitors
Note that SqMO is NOT the same as SqE, which is a later step in the pathway. Inhibitors of squalene epoxidase have found application mainly as antifungal drugs:[3]
Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.[5]
Localization
In 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 2,3;22,23-diepoxysqualene (DOS). DOS is converted to 24(S),25-epoxylanosterol by lanosterol synthase.
See also
References
- ^ "Entrez Gene: SQLE squalene epoxidase". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6713.
- ^ Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T (August 1997). "Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1". Genomics 44 (1): 141–3. doi:10.1006/geno.1997.4825. PMID 9286711.
- ^ Favre B, Ryder NS (February 1996). "Characterization of squalene epoxidase activity from the dermatophyte Trichophyton rubrum and its inhibition by terbinafine and other antimycotic agents". Antimicrob. Agents Chemother. 40 (2): 443–7. PMC 163131. PMID 8834895. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=8834895.
- ^ Ryder NS (February 1992). "Terbinafine: mode of action and properties of the squalene epoxidase inhibition". Br. J. Dermatol. 126 Suppl 39: 2–7. PMID 1543672.
- ^ Chugh A, Ray A, Gupta JB (January 2003). "Squalene epoxidase as hypocholesterolemic drug target revisited". Prog. Lipid Res. 42 (1): 37–50. doi:10.1016/S0163-7827(02)00029-2. PMID 12467639. http://linkinghub.elsevier.com/retrieve/pii/S0163782702000292.
Further reading
- Ma J, Dempsey AA, Stamatiou D, et al. (2007). "Identifying leukocyte gene expression patterns associated with plasma lipid levels in human subjects.". Atherosclerosis 191 (1): 63–72. doi:10.1016/j.atherosclerosis.2006.05.032. PMID 16806233.
- Laden BP, Tang Y, Porter TD (2000). "Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase.". Arch. Biochem. Biophys. 374 (2): 381–8. doi:10.1006/abbi.1999.1629. PMID 10666321.
- Helms MW, Kemming D, Pospisil H, et al. (2008). "Squalene epoxidase, located on chromosome 8q24.1, is upregulated in 8q+ breast cancer and indicates poor clinical outcome in stage I and II disease.". Br. J. Cancer 99 (5): 774–80. doi:10.1038/sj.bjc.6604556. PMC 2528137. PMID 18728668. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2528137.
- Nagai M, Sakakibara J, Nakamura Y, et al. (2002). "SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase.". Biochem. Biophys. Res. Commun. 295 (1): 74–80. doi:10.1016/S0006-291X(02)00623-X. PMID 12083769.
- Liu Y, Sun W, Zhang K, et al. (2007). "Identification of genes differentially expressed in human primary lung squamous cell carcinoma.". Lung Cancer 56 (3): 307–17. doi:10.1016/j.lungcan.2007.01.016. PMID 17316888.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=311072.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library.". Gene 200 (1-2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Lu Y, Dollé ME, Imholz S, et al. (2008). "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.". J. Lipid Res. 49 (12): 2582–9. doi:10.1194/jlr.M800232-JLR200. PMID 18660489.
- Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006.". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1347501.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Hartley JL, Temple GF, Brasch MA (2000). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948.
- Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.". Gene 138 (1-2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Nakamura Y, Sakakibara J, Izumi T, et al. (1996). "Transcriptional regulation of squalene epoxidase by sterols and inhibitors in HeLa cells.". J. Biol. Chem. 271 (14): 8053–6. doi:10.1074/jbc.271.14.8053. PMID 8626488.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Nagai M, Sakakibara J, Wakui K, et al. (1997). "Localization of the squalene epoxidase gene (SQLE) to human chromosome region 8q24.1.". Genomics 44 (1): 141–3. doi:10.1006/geno.1997.4825. PMID 9286711.
- Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline.". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528930.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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| Mevalonate pathway |
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| To cholesterol |
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| To Bile acids |
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