Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWQQ08W)

• DOT Name: Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B)
• Synonyms: 15-lipoxygenase 2; 15-LOX-2; Arachidonate 15-lipoxygenase B; 15-LOX-B; EC 1.13.11.33; Arachidonate 15-lipoxygenase type II; Linoleate 13-lipoxygenase 15-LOb; EC 1.13.11.-
• Gene Name: ALOX15B
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Carcinoma of esophagus
  Esophageal cancer
  Neoplasm of esophagus
  Precancerous condition
  Adenocarcinoma
  Breast neoplasm
  Colorectal neoplasm
  Head and neck cancer
  Head and neck carcinoma
  High blood pressure
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Prostate adenocarcinoma
  Prostate cancer
  Prostate neoplasm
  Psoriasis
  Advanced cancer
  Adrenal adenoma
  Aplasia cutis congenita
  Asthma
  Benign prostatic hyperplasia
  Colorectal carcinoma
  Coronary atherosclerosis
  Coronary heart disease
  Corpus callosum, agenesis of
  Pachyonychia congenita 3
  Prostate carcinoma
  Type-1 diabetes
• UniProt ID: LX15B_HUMAN
• PDB ID: 4NRE; 7LAF
• EC Number: 1.13.11.-; 1.13.11.33
• Pfam ID: PF00305 ; PF01477
• Sequence:
  MAEFRVRVSTGEAFGAGTWDKVSVSIVGTRGESPPLPLDNLGKEFTAGAEEDFQVTLPED
  VGRVLLLRVHKAPPVLPLLGPLAPDAWFCRWFQLTPPRGGHLLFPCYQWLEGAGTLVLQE
  GTAKVSWADHHPVLQQQRQEELQARQEMYQWKAYNPGWPHCLDEKTVEDLELNIKYSTAK
  NANFYLQAGSAFAEMKIKGLLDRKGLWRSLNEMKRIFNFRRTPAAEHAFEHWQEDAFFAS
  QFLNGLNPVLIRRCHYLPKNFPVTDAMVASVLGPGTSLQAELEKGSLFLVDHGILSGIQT
  NVINGKPQFSAAPMTLLYQSPGCGPLLPLAIQLSQTPGPNSPIFLPTDDKWDWLLAKTWV
  RNAEFSFHEALTHLLHSHLLPEVFTLATLRQLPHCHPLFKLLIPHTRYTLHINTLARELL
  IVPGQVVDRSTGIGIEGFSELIQRNMKQLNYSLLCLPEDIRTRGVEDIPGYYYRDDGMQI
  WGAVERFVSEIIGIYYPSDESVQDDRELQAWVREIFSKGFLNQESSGIPSSLETREALVQ
  YVTMVIFTCSAKHAAVSAGQFDSCAWMPNLPPSMQLPPPTSKGLATCEGFIATLPPVNAT
  CDVILALWLLSKEPGDQRPLGTYPDEHFTEEAPRRSIATFQSRLAQISRGIQERNQGLVL
  PYTYLDPPLIENSVSI
• Function: [Isoform A]: Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids (PUFAs) generating a spectrum of bioactive lipid mediators (Probable). It inserts peroxyl groups at C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing (15S)-hydroperoxyeicosatetraenoate/(15S)-HPETE (Probable). Also peroxidizes linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (Probable). Oxygenates arachidonyl derivatives such as 2-arachidonoylglycerol (2-AG) leading to the production and extracellular release of 15-hydroxyeicosatetraenoyl glycerol (15-HETE-G) that acts as a peroxisome proliferator-activated receptor alpha agonist. Has the ability to efficiently class-switch ALOX5 pro-inflammatory mediators into anti-inflammatory intermediates. Participates in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs) resolvin D5 ((7S,17S)-diHPDHA), which can actively down-regulate the immune response and have anti-aggregation properties with platelets. In addition to free PUFAs hydrolyzed from phospholipids, it directly oxidizes PUFAs esterified to membrane-bound phospholipids. Has no detectable 8S-lipoxygenase activity on arachidonate but reacts with (8S)-HPETE to produce (8S,15S)-diHPETE (Probable). 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 macrophage differentiation into proatherogenic foam cells ; [Isoform B]: Does not convert arachidonic acid to 15S-hydroperoxyeicosatetraenoic acid/(15S)-HPETE.
• Tissue Specificity: Expressed in hair, prostate, lung, ovary, lymph node, spinal cord and cornea.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
• Reactome Pathway: Synthesis of 15-eicosatetraenoic acid derivatives (R-HSA-2142770)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Biomarker	[1]
Atherosclerosis	DISMN9J3	Definitive	Biomarker	[1]
Carcinoma of esophagus	DISS6G4D	Definitive	Altered Expression	[2]
Esophageal cancer	DISGB2VN	Definitive	Altered Expression	[2]
Neoplasm of esophagus	DISOLKAQ	Definitive	Altered Expression	[2]
Precancerous condition	DISV06FL	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[5]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[6]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[6]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[10]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[11]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[12]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Adrenal adenoma	DISC2UN8	Limited	Genetic Variation	[14]
Aplasia cutis congenita	DISMDAYM	Limited	Altered Expression	[14]
Asthma	DISW9QNS	Limited	Altered Expression	[15]
Benign prostatic hyperplasia	DISI3CW2	Limited	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[16]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[17]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[17]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[14]
Pachyonychia congenita 3	DISZLC6C	Limited	Altered Expression	[18]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[9]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[19]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[20]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[20]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[21]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[23]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[24]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[28]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Polyunsaturated fatty acid lipoxygenase ALOX15B (ALOX15B).	[27]

References

• [1] Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS.J Biol Chem. 2016 Sep 9;291(37):19413-24. doi: 10.1074/jbc.M116.741454. Epub 2016 Jul 19.
• [2] Reduced 15S-lipoxygenase-2 expression in esophageal cancer specimens and cells and upregulation in vitro by the cyclooxygenase-2 inhibitor, NS398.Neoplasia. 2003 Mar-Apr;5(2):121-7. doi: 10.1016/s1476-5586(03)80003-9.
• [3] 15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa.J Invest Dermatol. 2001 Jul;117(1):36-43. doi: 10.1046/j.1523-1747.2001.01378.x.
• [4] Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.Prostaglandins Leukot Essent Fatty Acids. 2006 Apr;74(4):235-45. doi: 10.1016/j.plefa.2006.01.009. Epub 2006 Mar 23.
• [5] Expression of 15-lipoxygenase-1 in human colorectal cancer.Cancer Res. 1999 Jan 15;59(2):360-6.
• [6] Synergistic effect of 15-lipoxygenase 2 and radiation in killing head-and-neck cancer.Cancer Gene Ther. 2008 May;15(5):323-30. doi: 10.1038/cgt.2008.9. Epub 2008 Feb 22.
• [7] Positive feedback-loop of telomerase reverse transcriptase and 15-lipoxygenase-2 promotes pulmonary hypertension.PLoS One. 2013 Dec 23;8(12):e83132. doi: 10.1371/journal.pone.0083132. eCollection 2013.
• [8] 15-Lipoxygenase-2/15(S)-hydroxyeicosatetraenoic acid regulates cell proliferation and metastasis via the STAT3 pathway in lung adenocarcinoma.Prostaglandins Other Lipid Mediat. 2018 Sep;138:31-40. doi: 10.1016/j.prostaglandins.2018.07.003. Epub 2018 Aug 12.
• [9] Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.Cell Cycle. 2014;13(11):1798-810. doi: 10.4161/cc.28757. Epub 2014 Apr 14.
• [10] Genetic variation in the eicosanoid pathway is associated with non-small-cell lung cancer (NSCLC) survival.PLoS One. 2017 Jul 13;12(7):e0180471. doi: 10.1371/journal.pone.0180471. eCollection 2017.
• [11] Alterations in lipoxygenase and cyclooxygenase-2 catalytic activity and mRNA expression in prostate carcinoma.Neoplasia. 2001 Jul-Aug;3(4):287-303. doi: 10.1038/sj.neo.7900166.
• [12] 15-lipoxygenase 2 (15-LOX2) is a functional tumor suppressor that regulates human prostate epithelial cell differentiation, senescence, and growth (size).Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):135-46. doi: 10.1016/j.prostaglandins.2006.05.022. Epub 2006 Jul 7.
• [13] Lack of association of ALOX12 and ALOX15B polymorphisms with psoriasis despite altered urinary excretion of 12(S)-hydroxyeicosatetraenoic acid.Br J Dermatol. 2015 Feb;172(2):337-44. doi: 10.1111/bjd.13225. Epub 2014 Nov 30.
• [14] Loss of heterozygosity of 17p13, with possible involvement of ACADVL and ALOX15B, in the pathogenesis of adrenocortical tumors.Ann Surg. 2008 Jan;247(1):157-64. doi: 10.1097/SLA.0b013e318153ff55.
• [15] An ex vivo model of severe asthma using reconstituted human bronchial epithelium.J Allergy Clin Immunol. 2012 May;129(5):1259-1266.e1. doi: 10.1016/j.jaci.2012.01.073. Epub 2012 Mar 10.
• [16] Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis.Cancer Prev Res (Phila). 2010 Jul;3(7):829-38. doi: 10.1158/1940-6207.CAPR-09-0110. Epub 2010 Jun 22.
• [17] Association of polymorphisms in the ALOX15B gene with coronary artery disease.Clin Biochem. 2014 Apr;47(6):349-55. doi: 10.1016/j.clinbiochem.2013.12.013. Epub 2013 Dec 27.
• [18] 15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma.Oncogene. 2006 Sep 28;25(44):6015-25. doi: 10.1038/sj.onc.1209617. Epub 2006 May 8.
• [19] A regulatory role for -adrenergic receptors regarding the resolvin D1 (RvD1) pathway in the diabetic retina.PLoS One. 2017 Nov 2;12(11):e0185383. doi: 10.1371/journal.pone.0185383. eCollection 2017.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [23] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [24] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [25] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [26] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [27] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.