スクアレンモノオキシゲナーゼ
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| 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 |
[1] |
[2] |
|
|
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]
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:[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 Sqletm1a(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
- ^ "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. doi:10.1006/geno.1997.4825. PMID 9286711.
- ^ Sharpe LJ, Brown AJ (Jun 2013). "Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)". The Journal of Biological Chemistry 288 (26). doi:10.1074/jbc.R113.479808. PMID 23696639.
- ^ 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. doi:10.1111/j.1365-2133.1992.tb00001.x. PMID 1543672.
- ^ 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.
- ^ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Opthalmologica 88: 925-7.doi:10.1111/j.1755-3768.2010.4142.x: Wiley.
- ^ 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. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
- ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
- ^ 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.
- ^ 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, Sanger Institute Mouse Genetics Project, 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 (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. PMID 23870131.
- ^ 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. 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.
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Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)
|
|
| 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
|
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| 1.14.14: reduced flavin or flavoprotein |
|
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| 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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- Biochemistry overview
- Enzymes overview
- By EC number: 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism
|
|
| Mevalonate pathway |
| To HMG-CoA |
- Acetyl-Coenzyme A acetyltransferase
- HMG-CoA synthase (regulated step)
|
|
| 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
|
|
| Geranyl- |
- Dimethylallyltranstransferase
- Geranyl pyrophosphate
|
|
|
| To cholesterol |
| To lanosterol |
- Farnesyl-diphosphate farnesyltransferase
- Squalene monooxygenase
- Lanosterol synthase
|
|
| 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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|
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| To Bile acids |
- Cholesterol 7α-hydroxylase
- Sterol 27-hydroxylase
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| Steroidogenesis |
| To pregnenolone |
|
|
| To corticosteroids |
- aldosterone: 18-hydroxylase
- cortisol/cortisone: 17α-hydroxylase
- 11β dehydrogenase
- both: 3β dehydrogenase
- 21α-hydroxylase
- 11β-hydroxylase
|
|
| To sex hormones |
| To androgens |
- 17α-hydroxylase/17,20 lyase
- 3β dehydrogenase
- 17β dehydrogenase
- 5α reductase
|
|
| 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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Index of inborn errors of metabolism
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| Description |
- Metabolism
- Enzymes and pathways: citric acid cycle
- pentose phosphate
- glycoproteins
- glycosaminoglycans
- phospholipid
- cholesterol and steroid
- sphingolipids
- eicosanoids
- amino acid
- urea cycle
- nucleotide
|
|
| Disorders |
- Citric acid cycle and electron transport chain
- Glycoprotein
- Proteoglycan
- Fatty-acid
- Phospholipid
- Cholesterol and steroid
- Eicosanoid
- Amino acid
- Purine-pyrimidine
- Heme metabolism
- Symptoms and signs
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| Treatment |
|
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Index of hormones
|
|
| Description |
- Glands
- Hormones
- thyroid
- mineralocorticoids
- Physiology
- Development
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| Disease |
- Diabetes
- Congenital
- Neoplasms and cancer
- Other
- Symptoms and signs
|
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| Treatment |
- Procedures
- Drugs
- calcium balance
- corticosteroids
- oral hypoglycemics
- pituitary and hypothalamic
- thyroid
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UpToDate Contents
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English Journal
- Dysregulation of Plasmalogen Homeostasis Impairs Cholesterol Biosynthesis.
- Honsho M1, Abe Y1, Fujiki Y2.
- The Journal of biological chemistry.J Biol Chem.2015 Nov 27;290(48):28822-33. doi: 10.1074/jbc.M115.656983. Epub 2015 Oct 13.
- Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. However, physiological significance of the regulation of plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular plasmalogen lev
- PMID 26463208
- The Regulatory Domain of Squalene Monooxygenase Contains a Re-entrant Loop and Senses Cholesterol via a Conformational Change.
- Howe V1, Chua NK1, Stevenson J2, Brown AJ3.
- The Journal of biological chemistry.J Biol Chem.2015 Nov 13;290(46):27533-44. doi: 10.1074/jbc.M115.675181. Epub 2015 Oct 3.
- Squalene monooxygenase (SM) is an important control point in cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase. Although it is known to associate with the endoplasmic reticulum, its topology has not been determined. We have elucidated the membrane topology of the sterol-responsiv
- PMID 26434806
- Aspergillus niger Enhance Bioactive Compounds Biosynthesis As Well As Expression of Functional Genes in Adventitious Roots of Glycyrrhiza uralensis Fisch.
- Li J1,2, Wang J1, Li J1, Liu D3, Li H1, Gao W4, Li J5, Liu S5.
- Applied biochemistry and biotechnology.Appl Biochem Biotechnol.2015 Oct 21. [Epub ahead of print]
- In the present study, the culture conditions for the accumulation of Glycyrrhiza uralensis adventitious root metabolites in balloon-type bubble bioreactors (BTBBs) have been optimized. The results of the culture showed that the best culture conditions were a cone angle of 90° bioreactor and 0.4-0.6
- PMID 26490378
Japanese Journal
- Navigating the Shallows and Rapids of Cholesterol Synthesis Downstream of HMGCR
- Journal of Nutritional Science and Vitaminology 61(Supplement), S154-S156, 2015
- NAID 130005109890
- 生合成酵素反応機構の解析を基盤とする新規生物活性物質の探索
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Related Links
- スクアレンモノオキシゲナーゼ（squalene monooxygenase）またはスクアレンエポキシ ダーゼ（squalene epoxidase）は、NADPHと分子状酸素を用いスクアレンを2,3- オキシドスクアレン（スクアレンエポキシド）に酸化する酵素である。スクアレンモノ ...
- 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 ...
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