- Arachidonate 5-lipoxygenase
Arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or Alox5) is a human enzyme, member of the
lipoxygenase family. It transforms EFAs intoleukotrienes and is a current target for pharmaceutical intervention in a number of diseases.ubstrates and products
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.Functions
5-LO catalyzes oxidation of AA at the 5-position to yield
5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-LO then converts 5-HPETE toleukotriene A4 . [Reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R01595 R01595] and [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03058 R03058] at KEGG Pathway Database.]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
lipoxin s, respectively. [http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_a_56zPzhtm#12148909 Dorlands Medical Dictionary] , entries at "arachidonate 5-lipoxygenase" and following. Retrieved on 2006-02-07.]Clinical significance
5-LO is a target for pharmaceutical intervention in CAD.cite web |url=http://www.research.ucla.edu/tech/ucla01-429.htm |archiveurl=http://web.archive.org/web/20060830025600/http://www.research.ucla.edu/tech/ucla01-429.htm |archivedate=2006-08-30 |title=5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management |accessdate=2007-11-18 |publisher=UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2] Some people with variant
allele s for 5-LO are at elevated risk for CAD.cite journal |author=Dwyer JH, Allayee H, Dwyer KM, "et al" |title=Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis |journal=N. Engl. J. Med. |volume=350 |issue=1 |pages=29–37 |year=2004 |pmid=14702425 |doi=10.1056/NEJMoa025079] 5-LO is expressed in brain cells and may participate in neuropathologic processes. [cite journal |author=Zhang L, Zhang WP, Hu H, "et al" |title=Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma |journal=Neuropathology : official journal of the Japanese Society of Neuropathology |volume=26 |issue=2 |pages=99–106 |year=2006 |pmid=16708542 |doi=10.1111/j.1440-1789.2006.00658.x]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 withatherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [cite web | title = Entrez Gene: ALOX5 arachidonate 5-lipoxygenase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=240| accessdate = ]5-LO inhibitors
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 isZileuton .Minocycline , although primarily atetracycline antibiotic , is also a 5-LO inhibitor. can be used as DMARDS.cite journal | author=Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z | title=Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation | journal=Neuroreport | year=2004 | pages=2181–4 | volume=15 | issue=14 | pmid=15371729 | doi=10.1097/00001756-200410050-00007 ] It may therefore be used as aDMARD -medication in mildrheumatoid arthritis and otherrheumatic condition s. [ [http://arthritis.about.com/od/minocin/Minocin_Minocycline_Dosage_Side_Effects_Drug_Interactions.htm arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions] ]Activation
5-LO is activated by
5-lipoxygenase activating protein (FLAP).References
Further reading
PBB_Further_reading
citations =
*cite journal | author=Rådmark OP |title=The molecular biology and regulation of 5-lipoxygenase. |journal=Am. J. Respir. Crit. Care Med. |volume=161 |issue= 2 Pt 2 |pages= S11–5 |year= 2000 |pmid= 10673219 |doi=
*cite journal | author=Hammarberg T, Reddy KV, Persson B, Rådmark O |title=Calcium binding to 5-lipoxygenase. |journal=Adv. Exp. Med. Biol. |volume=507 |issue= |pages= 117–21 |year= 2003 |pmid= 12664574 |doi=
*cite journal | author=Ishii S, Noguchi M, Miyano M, "et al." |title=Mutagenesis studies on the amino acid residues involved in the iron-binding and the activity of human 5-lipoxygenase. |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 3 |pages= 1482–90 |year= 1992 |pmid= 1540191 |doi=
*cite journal | author=Nguyen T, Falgueyret JP, Abramovitz M, Riendeau D |title=Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase. |journal=J. Biol. Chem. |volume=266 |issue= 32 |pages= 22057–62 |year= 1991 |pmid= 1939225 |doi=
*cite journal | author=Hoshiko S, Rådmark O, Samuelsson B |title=Characterization of the human 5-lipoxygenase gene promoter. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue= 23 |pages= 9073–7 |year= 1991 |pmid= 2251250 |doi=
*cite journal | author=Funk CD, Hoshiko S, Matsumoto T, "et al." |title=Characterization of the human 5-lipoxygenase gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 8 |pages= 2587–91 |year= 1989 |pmid= 2565035 |doi=
*cite journal | author=Matsumoto T, Funk CD, Rådmark O, "et al." |title=Molecular cloning and amino acid sequence of human 5-lipoxygenase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 1 |pages= 26–30 |year= 1988 |pmid= 2829172 |doi=
*cite journal | author=Rouzer CA, Kargman S |title=Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187. |journal=J. Biol. Chem. |volume=263 |issue= 22 |pages= 10980–8 |year= 1988 |pmid= 3134355 |doi=
*cite journal | author=Dixon RA, Jones RE, Diehl RE, "et al." |title=Cloning of the cDNA for human 5-lipoxygenase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 2 |pages= 416–20 |year= 1988 |pmid= 3422434 |doi=
*cite journal | author=Jakobsson PJ, Shaskin P, Larsson P, "et al." |title=Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes. |journal=Eur. J. Biochem. |volume=232 |issue= 1 |pages= 37–46 |year= 1995 |pmid= 7556168 |doi=
*cite journal | author=Janssen-Timmen U, Vickers PJ, Wittig U, "et al." |title=Expression of 5-lipoxygenase in differentiating human skin keratinocytes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 15 |pages= 6966–70 |year= 1995 |pmid= 7624354 |doi=
*cite journal | author=Lepley RA, Fitzpatrick FA |title=5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins. |journal=J. Biol. Chem. |volume=269 |issue= 39 |pages= 24163–8 |year= 1994 |pmid= 7929073 |doi=
*cite journal | author=Shaw KJ, Ng C, Kovacs BW |title=Cyclooxygenase gene expression in human endometrium and decidua. |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=50 |issue= 5 |pages= 239–43 |year= 1994 |pmid= 8066098 |doi=
*cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=
*cite journal | author=Woods JW, Evans JF, Ethier D, "et al." |title=5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes. |journal=J. Exp. Med. |volume=178 |issue= 6 |pages= 1935–46 |year= 1993 |pmid= 8245774 |doi=
*cite journal | author=Mancini JA, Li C, Vickers PJ |title=5-Lipoxygenase activity in the human pancreas. |journal=Journal of lipid mediators |volume=8 |issue= 3 |pages= 145–50 |year= 1994 |pmid= 8268460 |doi=
*cite journal | author=VanderNoot VA, Fitzpatrick FA |title=Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2. |journal=Anal. Biochem. |volume=230 |issue= 1 |pages= 108–14 |year= 1996 |pmid= 8585605 |doi= 10.1006/abio.1995.1444
*cite journal | author=Brock TG, McNish RW, Bailie MB, Peters-Golden M |title=Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence. |journal=J. Biol. Chem. |volume=272 |issue= 13 |pages= 8276–80 |year= 1997 |pmid= 9079648 |doi=
*cite journal | author=Nassar GM, Montero A, Fukunaga M, Badr KF |title=Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes. |journal=Kidney Int. |volume=51 |issue= 5 |pages= 1520–8 |year= 1997 |pmid= 9150468 |doi=
*cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, "et al." |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=External links
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