Squalene monooxygenase

Squalene epoxidase
Chemical reaction catalyzed by squalene epoxidase.
Identifiers
EC number	1.14.13.132
CAS number	9029-62-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Squalene epoxidase
Identifiers
Symbols	SQLE ; FLJ30795
External IDs	OMIM: 602019 MGI: 109296 HomoloGene: 2355 IUPHAR: 2433 ChEMBL: 3592 GeneCards: SQLE Gene
EC number	1.14.13.132
Gene ontology Molecular function • squalene monooxygenase activity • flavin adenine dinucleotide binding Cellular component • endoplasmic reticulum membrane • integral component of membrane Biological process • cholesterol biosynthetic process • cellular aromatic compound metabolic process • response to organic substance • sterol biosynthetic process • small molecule metabolic process • oxidation-reduction process Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6713	20775
Ensembl	ENSG00000104549	ENSMUSG00000022351
UniProt	Q14534	P52019
RefSeq (mRNA)	NM_003129	NM_009270
RefSeq (protein)	NP_003120	NP_033296
Location (UCSC)	Chr 8: 125 – 125.02 Mb	Chr 15: 59.32 – 59.33 Mb
PubMed search

Squalene monooxygenase (also called squalene epoxidase) 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] Squalene monooxygenase (SqMO) was formerly referred to as squalene epoxidase (SqE) in the literature.^[3]

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

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 cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.^[6]

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 diepoxysqualene (DOS). DOS is converted to 24(S),25-epoxylanosterol by lanosterol synthase.

Model organisms

Model organisms have been used in the study of SQLE function. A conditional knockout mouse line called Sqle^{tm1a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.^[7] Male and female animals underwent a standardized phenotypic screen^[8] to determine the effects of deletion.^{[9][10][11][12]} Additional screens performed: - In-depth immunological phenotyping^[13]

Sqle knockout mouse phenotype

Characteristic	Phenotype
All data available at.[8][13]
Peripheral blood leukocytes 6 Weeks	Normal
Insulin	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Bone Marrow Immunophenotyping	Normal
Epidermal Immune Composition	Normal

See also

• Antifungal drug#Allylamines

References

1. "Entrez Gene: SQLE squalene epoxidase".
2. Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T (Aug 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.
3. Sharpe LJ, Brown AJ (Jun 2013). "Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)". The Journal of Biological Chemistry 288 (26): 18707–15. doi:10.1074/jbc.R113.479808. PMID 23696639.
4. Favre B, Ryder NS (Feb 1996). "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. PMC 163131. PMID 8834895.
5. Ryder NS (Feb 1992). "Terbinafine: mode of action and properties of the squalene epoxidase inhibition". The British Journal of Dermatology. 126 Suppl 39: 2–7. doi:10.1111/j.1365-2133.1992.tb00001.x. PMID 1543672.
6. Chugh A, Ray A, Gupta JB (Jan 2003). "Squalene epoxidase as hypocholesterolemic drug target revisited". Progress in Lipid Research 42 (1): 37–50. doi:10.1016/S0163-7827(02)00029-2. PMID 12467639.
7. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
8. "International Mouse Phenotyping Consortium".
9. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
10. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
11. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
12. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
13. "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

• Ma J, Dempsey AA, Stamatiou D, Marshall KW, Liew CC (Mar 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 (Feb 2000). "Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase". Archives of Biochemistry and Biophysics 374 (2): 381–8. doi:10.1006/abbi.1999.1629. PMID 10666321.
• Helms MW, Kemming D, Pospisil H, Vogt U, Buerger H, Korsching E, Liedtke C, Schlotter CM, Wang A, Chan SY, Brandt BH (Sep 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". British Journal of Cancer 99 (5): 774–80. doi:10.1038/sj.bjc.6604556. PMC 2528137. PMID 18728668.
• Nagai M, Sakakibara J, Nakamura Y, Gejyo F, Ono T (Jul 2002). "SREBP-2 and NF-Y are involved in the transcriptional regulation of squalene epoxidase". Biochemical and Biophysical Research Communications 295 (1): 74–80. doi:10.1016/S0006-291X(02)00623-X. PMID 12083769.
• 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 (Jun 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.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 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, van 't Slot R, Verschuren WM, Wijmenga C, Feskens EJ, Boer JM (Dec 2008). "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations". Journal of Lipid Research 49 (12): 2582–9. doi:10.1194/jlr.M800232-JLR200. PMID 18660489.
• 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 (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Maruyama K, Sugano S (Jan 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, Shibata A, Ono T (Apr 1996). "Transcriptional regulation of squalene epoxidase by sterols and inhibitors in HeLa cells". The Journal of Biological Chemistry 271 (14): 8053–6. doi:10.1074/jbc.271.14.8053. PMID 8626488.
• Nagai M, Sakakibara J, Wakui K, Fukushima Y, Igarashi S, Tsuji S, Arakawa M, Ono T (Aug 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, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.

External links

• Squalene monooxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.