関: 5-lipoxygenase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/05 07:41:40」(JST)

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Arachidonate 5-lipoxygenase also known as 5-lipoxygenase or 5-LO is an enzyme that in humans is encoded by the ALOX5 gene.^[1] Arachidonate 5-lipoxygenase is a member of the lipoxygenase family of enzymes. It transforms EFAs into leukotrienes and is a current target for pharmaceutical intervention in a number of diseases.

Substrates and products[edit]

EFA substrates and leukotriene products of 5-LO include:

Arachidonic acid (AA) yields the 4-series leukotrienes (LTB4, LTC4, LTD4, LTE4 — generally proinflammatory)
Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5 — antiinflammatory)
Gamma-linolenic acid (GLA via the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.

Function[edit]

5-LO catalyzes oxidation of AA at the 5-position to yield 5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-LO then converts 5-HPETE to leukotriene A4.^[2]

Eicosanoid synthesis.

Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, yielding 12- and 15-HPETE. These pathways lead to the leukotriene 12-hydroxyeicosatetraenoic acid (12-HETE) and to the lipoxins, respectively.^[3]

Clinical significance[edit]

5-LO is a target for pharmaceutical intervention in CAD.^[4] Some people with variant alleles for 5-LO are at elevated risk for CAD.^[5] 5-LO is expressed in brain cells and may participate in neuropathologic processes.^[6]

Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined.^[7]

5-LO inhibitors[edit]

As leukotrienes are important causes of pathological symptoms in asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is Zileuton. Minocycline, although primarily a tetracycline antibiotic, is also a 5-LO inhibitor.^[8] It may therefore be used as a DMARD-medication in mild rheumatoid arthritis and other rheumatic conditions.^[9]

Hyperforin, an active constituent of the herb St John's wort, is a highly potent 5-LO inhibitor.^[10]

Activation[edit]

5-LO is activated by 5-lipoxygenase activating protein (FLAP).

Interactions[edit]

Arachidonate 5-lipoxygenase has been shown to interact with Grb2^[11]^[12] and COTL1.^[13]

References[edit]

^ Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B (April 1989). "Characterization of the human 5-lipoxygenase gene". Proc. Natl. Acad. Sci. U.S.A. 86 (8): 2587–91. doi:10.1073/pnas.86.8.2587. PMC 286962. PMID 2565035.
^ Reaction R01595 and R03058 at KEGG Pathway Database.
^ Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.
^ "5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management". UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2. Archived from the original on 2006-08-30. Retrieved 2007-11-18.
^ Dwyer JH, Allayee H, Dwyer KM, et al. (2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis". N. Engl. J. Med. 350 (1): 29–37. doi:10.1056/NEJMoa025079. PMID 14702425.
^ Zhang L, Zhang WP, Hu H, et al. (2006). "Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma". Neuropathology : official journal of the Japanese Society of Neuropathology 26 (2): 99–106. doi:10.1111/j.1440-1789.2006.00658.x. PMID 16708542.
^ "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase".
^ can be used as DMARDS. Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z (2004). "Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation". Neuroreport 15 (14): 2181–4. doi:10.1097/00001756-200410050-00007. PMID 15371729.
^ arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions
^ Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. (December 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 15;64(12):1767-75. PMID 12445866
^ VanderNoot, V A; Fitzpatrick F A (September 1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Anal. Biochem. (UNITED STATES) 230 (1): 108–14. doi:10.1006/abio.1995.1444. ISSN 0003-2697. PMID 8585605.
^ Lepley, R A; Fitzpatrick F A (September 1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". J. Biol. Chem. (UNITED STATES) 269 (39): 24163–8. ISSN 0021-9258. PMID 7929073.
^ Provost, P; Doucet J, Hammarberg T, Gerisch G, Samuelsson B, Radmark O (May 2001). "5-Lipoxygenase interacts with coactosin-like protein". J. Biol. Chem. (United States) 276 (19): 16520–7. doi:10.1074/jbc.M011205200. ISSN 0021-9258. PMID 11297527.

External links[edit]

Arachidonate 5-Lipoxygenase at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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English Journal

Metabolomic and transcriptomic profiling of human K-ras oncogene transgenic rats with pancreatic ductal adenocarcinomas.

Yabushita S, Fukamachi K, Tanaka H, Fukuda T, Sumida K, Deguchi Y, Mikata K, Nishioka K, Kawamura S, Uwagawa S, Suzui M, Alexander DB, Tsuda H.SourceEnvironmental Health Science Laboratory, Sumitomo Chemical Co., Osaka 554-8558, Japan.
Carcinogenesis.Carcinogenesis.2013 Jun;34(6):1251-9. doi: 10.1093/carcin/bgt053. Epub 2013 Feb 7.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most debilitating malignancies in humans, and one of the reasons for this is the inability to diagnose this disease early in its development. To search for biomarkers that can be used for early diagnosis of PDAC, we established a rat model of hum
PMID 23393225

OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells.

Sarveswaran S, Ghosh J.SourceVattikuti Urology Institute, Henry Ford Health System, Detroit, MI 48202, United States.
Cancer letters.Cancer Lett.2013 May 2. pii: S0304-3835(13)00361-3. doi: 10.1016/j.canlet.2013.04.027. [Epub ahead of print]
Inhibition of 5-Lox induces apoptosis in prostate cancer cells by inactivating PKCε which is prevented by 5-oxoETE, and activators of PKCε prevent 5-Lox inhibition-induced apoptosis, suggesting that 5-Lox metabolites exert survival signaling via PKCε. However, mechanisms by which 5-Lox metabolite
PMID 23643940

Overexpression of 5-lipoxygenase and its relation with cell proliferation and angiogenesis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinogenesis.

Chatterjee M, Das S, Roy K, Chatterjee M.SourceChemical Carcinogenesis and Chemoprevention Laboratory, Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India.
Molecular carcinogenesis.Mol Carcinog.2013 May;52(5):359-69. doi: 10.1002/mc.21858. Epub 2011 Dec 28.
The present study was performed to investigate the critical role of 5-lipoxygenase (5-LOX) in 7,12-dimethylbenz(α)anthracene (DMBA)-induced rat mammary inflammation associated carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(α)anthracene (DMBA; 0.5 m
PMID 22213124

Japanese Journal

Expression Analysis of Leukotriene-Inflammatory Gene Interaction Network in Patients with Coronary Artery Disease

, , , ,
Journal of Atherosclerosis and Thrombosis 21(4), 329-345, 2014
… We aimed to construct a network of interactions between leukotrienes and inflammatory biomarkers and evaluate the expression of key members of the leukotriene pathway and leukotriene-induced inflammatory molecules in patients with coronary artery disease(CAD) and healthy controls.Methods: Leukotrienes and their regulatory inflammatory molecules reported in the literature were used to construct a biological network employing Gene spring GX v12.5. …
NAID 130004444722

Preliminary assessment of differential expression of candidate genes associated with atherosclerosis

, , [他], , ,
Genes & Genetic Systems 88(3), 199-209, 2013
… 11 candidate genes, namely tumor protein (TP53), transforming growth factor, beta receptor II (TGFBR2), cysthathionenine-beta-synthase (CBS), insulin receptor substrate 1 (IRS1), lipoprotein lipase (LPL), methylenetetrahydrofolate reductase (MTHFR), thrombomodulin (THBD), lecithin-cholesterol acyltransferase (LCAT), matrix metallopeptidase 9 (MMP9), low density lipoprotein receptor (LDLR), and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) genes associated with …
NAID 130003361009

Detection of 5-Lipoxygenase Activity in the Liverwort Marchantia polyrnorpha L.

, ,
Bioscience, biotechnology, and biochemistry 73(11), 2549-2551, 2009-11-23
… We detected 5-LOX (arachidonate 5-lipoxygenase) in the homogenate of <I>Marchantia polymorpha</I> … LC/MS/MS analysis indicated that the liverwort 5-LOX produced 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HPETE) with arachidonic acid as a substrate. … The 5-LOX activity showed a Ca<SUP>2+</SUP> …
NAID 10027548337

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リンク元	「アラキドン酸5-リポキシゲナーゼ」
関連記事	「arachidonate」「lipoxygenase」

「アラキドン酸5-リポキシゲナーゼ」

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arachidonate 5-lipoxygenase
Identifiers
EC number	1.13.11.34
CAS number	80619-02-9
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
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PDB structures	RCSB PDB PDBe PDBsum
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Arachidonate 5-lipoxygenase
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	3O8Y, 3V92, 3V98, 3V99
Identifiers
Symbols	ALOX5; 5-LO; 5-LOX; 5LPG; LOG5
External IDs	OMIM: 152390 MGI: 87999 HomoloGene: 561 ChEMBL: 215 GeneCards: ALOX5 Gene
EC number	1.13.11.34
Gene Ontology
Molecular function	• arachidonate 5-lipoxygenase activity; • iron ion binding; • protein binding; • lipoxygenase activity;
Cellular component	• nuclear envelope; • nuclear envelope lumen; • cytosol; • nuclear matrix; • nuclear membrane;
Biological process	• leukotriene production involved in inflammatory response; • leukotriene metabolic process; • arachidonic acid metabolic process; • leukotriene biosynthetic process; • lipoxygenase pathway; • small molecule metabolic process; • lipoxin metabolic process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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　　[★]

英: arachidonate 5-lipoxygenase
関: 5-リポキシゲナーゼ

「arachidonate」

　　[★] アラキドン酸、アラキドン酸エステル

関: AA、arachidonic acid

「lipoxygenase」

　　[★] リポキシゲナーゼ, 不飽和脂肪酸酸化酵素, LOX

[pmid2565035-1] Funk CD, Hoshiko S, Matsumoto T, Rdmark O, Samuelsson B (April 1989). "Characterization of the human 5-lipoxygenase gene". Proc. Natl. Acad. Sci. U.S.A. 86 (8): 2587–91. doi:10.1073/pnas.86.8.2587. PMC 286962. PMID 2565035.

[2] Reaction R01595 and R03058 at KEGG Pathway Database.

[dorland-3] Dorlands Medical Dictionary, entries at arachidonate 5-lipoxygenase and following. Retrieved on 2006-02-07.

[ucla-4] "5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management". UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2. Archived from the original on 2006-08-30. Retrieved 2007-11-18.

[dwyer-5] Dwyer JH, Allayee H, Dwyer KM, et al. (2004). "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis". N. Engl. J. Med. 350 (1): 29–37. doi:10.1056/NEJMoa025079. PMID 14702425.

[6] Zhang L, Zhang WP, Hu H, et al. (2006). "Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma". Neuropathology : official journal of the Japanese Society of Neuropathology 26 (2): 99–106. doi:10.1111/j.1440-1789.2006.00658.x. PMID 16708542.

[7] "Entrez Gene: ALOX5 arachidonate 5-lipoxygenase".

[Note4-8] used as DMARDS. Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z (2004). "Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation". Neuroreport 15 (14): 2181–4. doi:10.1097/00001756-200410050-00007. PMID 15371729.

[9] rthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions

[10] Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. (December 2002). "Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase". Biochemical Pharmacology. 15;64(12):1767-75. PMID 12445866

[pmid8585605-11] VanderNoot, V A; Fitzpatrick F A (September 1995). "Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2". Anal. Biochem. (UNITED STATES) 230 (1): 108–14. doi:10.1006/abio.1995.1444. ISSN 0003-2697. PMID 8585605.

[pmid7929073-12] Lepley, R A; Fitzpatrick F A (September 1994). "5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins". J. Biol. Chem. (UNITED STATES) 269 (39): 24163–8. ISSN 0021-9258. PMID 7929073.

[pmid11297527-13] Provost, P; Doucet J, Hammarberg T, Gerisch G, Samuelsson B, Radmark O (May 2001). "5-Lipoxygenase interacts with coactosin-like protein". J. Biol. Chem. (United States) 276 (19): 16520–7. doi:10.1074/jbc.M011205200. ISSN 0021-9258. PMID 11297527.

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arachidonate 5-lipoxygenase