Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0DH40W)

• DOT Name: Arachidonate 5-lipoxygenase-activating protein (ALOX5AP)
• Synonyms: FLAP; MK-886-binding protein
• Gene Name: ALOX5AP
• UniProt ID: AL5AP_HUMAN
• PDB ID: 2Q7M; 2Q7R; 6VGC; 6VGI
• Pfam ID: PF01124
• Sequence:
  MDQETVGNVVLLAIVTLISVVQNGFFAHKVEHESRTQNGRSFQRTGTLAFERVYTANQNC
  VDAYPTFLAVLWSAGLLCSQVPAAFAGLMYLFVRQKYFVGYLGERTQSTPGYIFGKRIIL
  FLFLMSVAGIFNYYLIFFFGSDFENYIKTISTTISPLLLIP
• Function: Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.
• KEGG Pathway: Fc epsilon RI sig.ling pathway (hsa04664)
• Reactome Pathway:
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Synthesis of Lipoxins (LX) (R-HSA-2142700)
  Synthesis of 5-eicosatetraenoic acids (R-HSA-2142688)
• BioCyc Pathway: MetaCyc:ENSG00000132965-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[8]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[9]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[11]
Warfarin	DMJYCVW	Approved	Warfarin increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[12]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[2]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[15]
MK-886	DMT0O7H	Discontinued in Phase 2	MK-886 decreases the activity of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[17]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[18]

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 Arachidonate 5-lipoxygenase-activating protein (ALOX5AP).	[14]

References

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• [2] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
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• [5] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [10] A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle. PLoS One. 2006 Dec 20;1(1):e97. doi: 10.1371/journal.pone.0000097.
• [11] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [12] Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8161-6. doi: 10.1073/pnas.0602414103. Epub 2006 May 12.
• [13] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Toxicity of human monocytic THP-1 cells and microglia toward SH-SY5Y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein FLAP. J Leukoc Biol. 2003 Mar;73(3):369-78.
• [17] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [18] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.