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| Squalene epoxidase |
|
Chemical reaction catalyzed by squalene epoxidase.
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| 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 |
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| SQLE |
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| Identifiers |
| Aliases |
SQLE, entrez:6713, squalene epoxidase |
| External IDs |
OMIM: 602019 MGI: 109296 HomoloGene: 2355 GeneCards: SQLE |
| Gene ontology |
| Molecular function |
• oxidoreductase activity
• flavin adenine dinucleotide binding
• squalene monooxygenase activity
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| Cellular component |
• organelle membrane
• integral component of membrane
• endoplasmic reticulum membrane
• membrane
• intracellular membrane-bounded organelle
• endoplasmic reticulum
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| Biological process |
• cellular aromatic compound metabolic process
• cholesterol biosynthetic process
• oxidation-reduction process
• response to organic substance
• cholesterol metabolic process
• sterol biosynthetic process
• regulation of cholesterol biosynthetic process
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| Sources:Amigo / QuickGO |
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| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
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| Ensembl |
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| UniProt |
|
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| RefSeq (mRNA) |
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| RefSeq (protein) |
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| Location (UCSC) |
Chr 8: 125 – 125.02 Mb |
Chr 15: 59.32 – 59.33 Mb |
| PubMed search |
[1] |
[2] |
| Wikidata |
| View/Edit Human |
View/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.[3] In humans, squalene epoxidase is encoded by the SQLE gene.[4] Squalene monooxygenase (SqMO) was formerly referred to as squalene epoxidase (SqE) in the literature.[5]
Contents
- 1 Mechanism
- 2 Inhibitors
- 3 Localization
- 4 Additional products
- 5 Model organisms
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
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:[6]
- butenafine
- naftifine
- terbinafine[7]
Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia.[8]
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.[9] Male and female animals underwent a standardized phenotypic screen[10] to determine the effects of deletion.[11][12][13][14] Additional screens performed: - In-depth immunological phenotyping[15]
Sqle knockout mouse phenotype
| Characteristic |
Phenotype |
| All data available at.[10][15] |
| 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
- ^ "Human PubMed Reference:".
- ^ "Mouse PubMed Reference:".
- ^ "Entrez Gene: SQLE squalene epoxidase".
- ^ 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. PMID 9286711. doi:10.1006/geno.1997.4825.
- ^ 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. PMC 3696645 . PMID 23696639. doi:10.1074/jbc.R113.479808.
- ^ 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.
- ^ 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. PMID 1543672. doi:10.1111/j.1365-2133.1992.tb00001.x.
- ^ Chugh A, Ray A, Gupta JB (Jan 2003). "Squalene epoxidase as hypocholesterolemic drug target revisited". Progress in Lipid Research. 42 (1): 37–50. PMID 12467639. doi:10.1016/S0163-7827(02)00029-2.
- ^ 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.
- ^ a b "International Mouse Phenotyping Consortium".
- ^ 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. PMC 3572410 . PMID 21677750. doi:10.1038/nature10163.
- ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. PMID 21677718. doi:10.1038/474262a.
- ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. PMID 17218247. doi:10.1016/j.cell.2006.12.018.
- ^ 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. PMC 3717207 . PMID 23870131. doi:10.1016/j.cell.2013.06.022.
- ^ a b "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. PMID 16806233. doi:10.1016/j.atherosclerosis.2006.05.032.
- 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. PMID 10666321. doi: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 (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. PMC 2528137 . PMID 18728668. doi:10.1038/sj.bjc.6604556.
- 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. PMID 12083769. doi: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 (Jun 2007). "Identification of genes differentially expressed in human primary lung squamous cell carcinoma". Lung Cancer. 56 (3): 307–17. PMID 17316888. doi:10.1016/j.lungcan.2007.01.016.
- 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. PMID 9373149. doi: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 (Dec 2008). "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations". Journal of Lipid Research. 49 (12): 2582–9. PMID 18660489. doi:10.1194/jlr.M800232-JLR200.
- 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. PMC 1347501 . PMID 16381901. doi:10.1093/nar/gkj139.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. PMC 310948 . PMID 11076863. doi:10.1101/gr.143000.
- 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. PMID 8125298. doi:10.1016/0378-1119(94)90802-8.
- 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. PMID 8626488. doi:10.1074/jbc.271.14.8053.
- 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. PMID 9286711. doi: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 (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. PMC 528930 . PMID 15489336. doi:10.1101/gr.2576704.
External links
- Squalene monooxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)
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Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism
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| Mevalonate pathway |
| To HMG-CoA |
- Acetyl-Coenzyme A acetyltransferase
- HMG-CoA synthase (regulated step)
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| Ketogenesis |
- HMG-CoA lyase
- 3-hydroxybutyrate dehydrogenase
- Thiophorase
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| To Mevalonic acid |
|
| To DMAPP |
- Mevalonate kinase
- Phosphomevalonate kinase
- Pyrophosphomevalonate decarboxylase
- Isopentenyl-diphosphate delta isomerase
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| Geranyl- |
- Dimethylallyltranstransferase
- Geranyl pyrophosphate
|
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| To cholesterol |
| To lanosterol |
- Farnesyl-diphosphate farnesyltransferase
- Squalene monooxygenase
- Lanosterol synthase
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| 7-Dehydrocholesterol path |
- Lanosterol 14α-demethylase
- Sterol-C5-desaturase-like
- 7-Dehydrocholesterol reductase
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| Desmosterol path |
- 24-dehydrocholesterol reductase
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| To Bile acids |
- Cholesterol 7α-hydroxylase
- Sterol 27-hydroxylase
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| Steroidogenesis |
| To pregnenolone |
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| To corticosteroids |
- aldosterone: 18-hydroxylase
- cortisol/cortisone: 17α-hydroxylase
- 11β dehydrogenase
- both: 3β dehydrogenase
- 21α-hydroxylase
- 11β-hydroxylase
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| To sex hormones |
| To androgens |
- 17α-hydroxylase/17,20 lyase
- 3β dehydrogenase
- 17β dehydrogenase
- 5α reductase
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| To estrogens |
|
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| Other/ungrouped |
- Steroid metabolism: sulfatase
- sulfotransferase
- Steroidogenic acute regulatory protein
- Cholesterol total synthesis
- Reverse cholesterol transport
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Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)
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| 1.14.11: 2-oxoglutarate |
- Prolyl hydroxylase
- Lysyl hydroxylase
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| 1.14.13: NADH or NADPH |
- Flavin-containing monooxygenase
- Nitric oxide synthase
- Cholesterol 7 alpha-hydroxylase
- Methane monooxygenase
- 3A4
- Lanosterol 14 alpha-demethylase
- 24-hydroxycholesterol 7α-hydroxylase
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| 1.14.14: reduced flavin or flavoprotein |
|
| 1.14.15: reduced iron-sulfur protein |
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| 1.14.16: reduced pteridine (BH4 dependent) |
- Phenylalanine hydroxylase
- Tyrosine hydroxylase
- Tryptophan hydroxylase
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| 1.14.17: reduced ascorbate |
- Dopamine beta-hydroxylase
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| 1.14.18-19: other |
- Tyrosinase
- Stearoyl-CoA desaturase-1
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| 1.14.99 - miscellaneous |
- Cyclooxygenase
- Heme oxygenase (HMOX1)
- Squalene monooxygenase
- 17A1
- 21A2
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Enzymes
|
| Activity |
- Active site
- Binding site
- Catalytic triad
- Oxyanion hole
- Enzyme promiscuity
- Catalytically perfect enzyme
- Coenzyme
- Cofactor
- Enzyme catalysis
|
| Regulation |
- Allosteric regulation
- Cooperativity
- Enzyme inhibitor
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| Classification |
- EC number
- Enzyme superfamily
- Enzyme family
- List of enzymes
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| Kinetics |
- Enzyme kinetics
- Eadie–Hofstee diagram
- Hanes–Woolf plot
- Lineweaver–Burk plot
- Michaelis–Menten kinetics
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| Types |
- EC1 Oxidoreductases (list)
- EC2 Transferases (list)
- EC3 Hydrolases (list)
- EC4 Lyases (list)
- EC5 Isomerases (list)
- EC6 Ligases (list)
|
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
UpToDate Contents
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English Journal
- In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study.
- Karumuri S1, Singh PK2, Shukla P2.
- Indian journal of microbiology.Indian J Microbiol.2015 Sep;55(3):333-40. doi: 10.1007/s12088-015-0524-x. Epub 2015 Apr 1.
- The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid
- PMID 26063944
- Production of squalene by lactose-fermenting yeast Kluyveromyces lactis with reduced squalene epoxidase activity.
- Drozdíková E1, Garaiová M2, Csáky Z2, Obernauerová M1, Hapala I2.
- Letters in applied microbiology.Lett Appl Microbiol.2015 Jul;61(1):77-84. doi: 10.1111/lam.12425. Epub 2015 May 10.
- Utilization of yeast as squalene source for commercial use is limited by relatively high production costs. The ability of Kluyveromyces lactis to grow on cheap lactose-containing diary industry wastes could improve the economy of the production process. We therefore tested the potential of this yeas
- PMID 25864715
Japanese Journal
- Lower Squalene Epoxidase and Higher Scavenger Receptor Class B Type 1 Protein Levels Are Involved in Reduced Serum Cholesterol Levels in Stroke-Prone Spontaneously Hypertensive Rats
- メダカゲノム情報によるステロール生合成遺伝子の解析 : メダカSqualene epoxidaseの遺伝子構造
- 福岡教育大学紀要. 第3分冊, 数学・理科・技術科編 = Bulletin of Fukuoka University of Education. 福岡教育大学 編 (62), 49-60, 2013
- NAID 40019621235
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