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 / QuickGO
SQLE
Identifiers
AliasesSQLE, entrez:6713, squalene epoxidase
External IDsOMIM: 602019 MGI: 109296 HomoloGene: 2355 GeneCards: SQLE
Gene location (Human)
Chr.Chromosome 8 (human)[1]
Band8q24.13Start124,998,497 bp[1]
End125,022,283 bp[1]
Orthologs
SpeciesHumanMouse
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 MbChr 15: 59.32 – 59.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] In humans, squalene epoxidase is encoded by the SQLE gene.[6] Squalene monooxygenase (SqMO) was formerly referred to as squalene epoxidase (SqE) in the literature.[7]

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:[8]

Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.[10]

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 Sqletm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping[17]

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000104549 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022351 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ "Entrez Gene: SQLE squalene epoxidase".
  6. ↑ 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.
  7. ↑ 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. PMC 3696645. PMID 23696639.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 "International Mouse Phenotyping Consortium".
  13. ↑ 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.
  14. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  15. ↑ 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.
  16. ↑ 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.
  17. 1 2 "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.

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