| Structural highlights
Function
[LX15B_HUMAN] Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Converts arachidonic acid to 15S-hydroperoxyeicosatetraenoic acid/(15S)-HPETE. Also acts on linoleic acid to produce 13-hydroxyoctadecadienoic acid/13-HPODE. Has no detectable 8S-lipoxygenase activity but reacts with (8S)-HPETE to produce (8S,15S)-diHPETE. May regulate progression through the cell cycle and cell proliferation. May also regulate cytokine secretion by macrophages and therefore play a role in the immune response. May also regulate macrophages differentiation into proatherogenic foam cells.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Atherosclerosis is associated with chronic inflammation occurring over decades. The enzyme 15-lipoxygenase-2 (15-LOX-2) is highly expressed in large atherosclerotic plaques, and its activity has been linked to the progression of macrophages to the lipid-laden foam cells present in atherosclerotic plaques. We report here the crystal structure of human 15-LOX-2 in complex with an inhibitor that appears to bind as a substrate mimic. 15-LOX-2 contains a long loop, composed of hydrophobic amino acids, which projects from the amino-terminal membrane-binding domain. The loop is flanked by two Ca(2+)-binding sites that confer Ca(2+)-dependent membrane binding. A comparison of the human 15-LOX-2 and 5-LOX structures reveals similarities at the active sites, as well striking differences that can be exploited for design of isoform-selective inhibitors.
The structure of human 15-lipoxygenase-2 with a substrate mimic.,Kobe MJ, Neau DB, Mitchell CE, Bartlett SG, Newcomer ME J Biol Chem. 2014 Mar 21;289(12):8562-9. doi: 10.1074/jbc.M113.543777. Epub 2014 , Feb 4. PMID:24497644[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tang S, Bhatia B, Maldonado CJ, Yang P, Newman RA, Liu J, Chandra D, Traag J, Klein RD, Fischer SM, Chopra D, Shen J, Zhau HE, Chung LW, Tang DG. Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells. J Biol Chem. 2002 May 3;277(18):16189-201. Epub 2002 Feb 11. PMID:11839751 doi:http://dx.doi.org/10.1074/jbc.M111936200
- ↑ Jisaka M, Kim RB, Boeglin WE, Brash AR. Identification of amino acid determinants of the positional specificity of mouse 8S-lipoxygenase and human 15S-lipoxygenase-2. J Biol Chem. 2000 Jan 14;275(2):1287-93. PMID:10625675
- ↑ Bhatia B, Maldonado CJ, Tang S, Chandra D, Klein RD, Chopra D, Shappell SB, Yang P, Newman RA, Tang DG. Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants. J Biol Chem. 2003 Jul 4;278(27):25091-100. Epub 2003 Apr 18. PMID:12704195 doi:http://dx.doi.org/10.1074/jbc.M301920200
- ↑ Jisaka M, Iwanaga C, Takahashi N, Goto T, Kawada T, Yamamoto T, Ikeda I, Nishimura K, Nagaya T, Fushiki T, Yokota K. Double dioxygenation by mouse 8S-lipoxygenase: specific formation of a potent peroxisome proliferator-activated receptor alpha agonist. Biochem Biophys Res Commun. 2005 Dec 9;338(1):136-43. Epub 2005 Aug 15. PMID:16112079 doi:http://dx.doi.org/10.1016/j.bbrc.2005.08.029
- ↑ Danielsson KN, Rydberg EK, Ingelsten M, Akyurek LM, Jirholt P, Ullstrom C, Forsberg GB, Boren J, Wiklund O, Hulten LM. 15-Lipoxygenase-2 expression in human macrophages induces chemokine secretion and T cell migration. Atherosclerosis. 2008 Jul;199(1):34-40. Epub 2007 Dec 11. PMID:18067895 doi:http://dx.doi.org/10.1016/j.atherosclerosis.2007.10.027
- ↑ Magnusson LU, Lundqvist A, Karlsson MN, Skalen K, Levin M, Wiklund O, Boren J, Hulten LM. Arachidonate 15-lipoxygenase type B knockdown leads to reduced lipid accumulation and inflammation in atherosclerosis. PLoS One. 2012;7(8):e43142. doi: 10.1371/journal.pone.0043142. Epub 2012 Aug 17. PMID:22912809 doi:http://dx.doi.org/10.1371/journal.pone.0043142
- ↑ Kobe MJ, Neau DB, Mitchell CE, Bartlett SG, Newcomer ME. The structure of human 15-lipoxygenase-2 with a substrate mimic. J Biol Chem. 2014 Mar 21;289(12):8562-9. doi: 10.1074/jbc.M113.543777. Epub 2014 , Feb 4. PMID:24497644 doi:http://dx.doi.org/10.1074/jbc.M113.543777
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