General Information of Drug Off-Target (DOT) (ID: OTFL5KR5)

DOT Name Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12)
Synonyms
EC 1.13.11.-; Arachidonate (12S)-lipoxygenase; 12S-LOX; 12S-lipoxygenase; EC 1.13.11.31; Arachidonate (15S)-lipoxygenase; EC 1.13.11.33; Linoleate (13S)-lipoxygenase; Lipoxin synthase 12-LO; EC 3.3.2.-; Platelet-type lipoxygenase 12
Gene Name ALOX12
UniProt ID
LOX12_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3D3L; 8GHB; 8GHC; 8GHD; 8GHE
EC Number
1.13.11.-; 1.13.11.31; 1.13.11.33; 3.3.2.-
Pfam ID
PF00305 ; PF01477
Sequence
MGRYRIRVATGAWLFSGSYNRVQLWLVGTRGEAELELQLRPARGEEEEFDHDVAEDLGLL
QFVRLRKHHWLVDDAWFCDRITVQGPGACAEVAFPCYRWVQGEDILSLPEGTARLPGDNA
LDMFQKHREKELKDRQQIYCWATWKEGLPLTIAADRKDDLPPNMRFHEEKRLDFEWTLKA
GALEMALKRVYTLLSSWNCLEDFDQIFWGQKSALAEKVRQCWQDDELFSYQFLNGANPML
LRRSTSLPSRLVLPSGMEELQAQLEKELQNGSLFEADFILLDGIPANVIRGEKQYLAAPL
VMLKMEPNGKLQPMVIQIQPPNPSSPTPTLFLPSDPPLAWLLAKSWVRNSDFQLHEIQYH
LLNTHLVAEVIAVATMRCLPGLHPIFKFLIPHIRYTMEINTRARTQLISDGGIFDKAVST
GGGGHVQLLRRAAAQLTYCSLCPPDDLADRGLLGLPGALYAHDALRLWEIIARYVEGIVH
LFYQRDDIVKGDPELQAWCREITEVGLCQAQDRGFPVSFQSQSQLCHFLTMCVFTCTAQH
AAINQGQLDWYAWVPNAPCTMRMPPPTTKEDVTMATVMGSLPDVRQACLQMAISWHLSRR
QPDMVPLGHHKEKYFSGPKPKAVLNQFRTDLEKLEKEITARNEQLDWPYEYLKPSCIENS
VTI
Function
Catalyzes the regio and stereo-specific incorporation of molecular oxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species. Mainly converts arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to the specific bioactive lipid (12S)-hydroperoxyeicosatetraenoate/(12S)-HPETE. Through the production of bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation. It can also catalyze the epoxidation of double bonds of polyunsaturated fatty acids such as (14S)-hydroperoxy-docosahexaenoate/(14S)-HPDHA resulting in the formation of (13S,14S)-epoxy-DHA. Furthermore, it may participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs) like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets. An additional function involves a multistep process by which it transforms leukotriene A4/LTA4 into the bioactive lipids lipoxin A4/LXA4 and lipoxin B4/LXB4, both are vasoactive and LXA4 may regulate neutrophil function via occupancy of specific recognition sites. Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to (13S)-hydroperoxyoctadecadienoate/ (13S-HPODE). Due to its role in regulating both the expression of the vascular endothelial growth factor (VEGF, an angiogenic factor involved in the survival and metastasis of solid tumors) and the expression of integrin beta-1 (known to affect tumor cell migration and proliferation), it can be regarded as protumorigenic. Important for cell survival, as it may play a role not only in proliferation but also in the prevention of apoptosis in vascular smooth muscle cells.
Tissue Specificity Expressed in vascular smooth muscle cells.
KEGG Pathway
Arachidonic acid metabolism (hsa00590 )
Metabolic pathways (hsa01100 )
Antifolate resistance (hsa01523 )
Serotonergic sy.pse (hsa04726 )
Inflammatory mediator regulation of TRP channels (hsa04750 )
Reactome Pathway
Synthesis of Lipoxins (LX) (R-HSA-2142700 )
Synthesis of 12-eicosatetraenoic acid derivatives (R-HSA-2142712 )
Biosynthesis of DHA-derived SPMs (R-HSA-9018677 )
Biosynthesis of DPAn-6 SPMs (R-HSA-9025106 )
Biosynthesis of DPAn-3-derived maresins (R-HSA-9026290 )
Synthesis of Hepoxilins (HX) and Trioxilins (TrX) (R-HSA-2142696 )
BioCyc Pathway
MetaCyc:HS03167-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Bortezomib DMNO38U Approved Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12) increases the response to substance of Bortezomib. [10]
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This DOT Affected the Regulation of Drug Effects of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Arachidonic acid DMUOQZD Investigative Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12) increases the metabolism of Arachidonic acid. [1]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Quercetin DM3NC4M Approved Quercetin decreases the activity of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [1]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [2]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [3]
Hydroquinone DM6AVR4 Approved Hydroquinone increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [4]
Fenofibrate DMFKXDY Approved Fenofibrate increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [5]
Masoprocol DMMVNZ0 Approved Masoprocol decreases the activity of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [1]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the activity of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [1]
BAICALEIN DM4C7E6 Phase 2 BAICALEIN decreases the activity of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [1]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [7]
D-glucose DMMG2TO Investigative D-glucose increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [8]
Kaempferol DMHEMUB Investigative Kaempferol decreases the activity of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [1]
PAF DMRZAQW Investigative PAF increases the expression of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [9]
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⏷ Show the Full List of 12 Drug(s)
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 affects the methylation of Polyunsaturated fatty acid lipoxygenase ALOX12 (ALOX12). [6]
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References

1 Assessing 12(S)-lipoxygenase inhibitory activity using colorectal cancer cells overexpressing the enzyme. Food Chem Toxicol. 2007 Mar;45(3):508-14. doi: 10.1016/j.fct.2006.08.013. Epub 2006 Aug 30.
2 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
3 The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
4 Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
5 Differential effects of peroxisome proliferator-activated receptor activators on the mRNA levels of genes involved in lipid metabolism in primary human monocyte-derived macrophages. Metabolism. 2003 May;52(5):652-7. doi: 10.1053/meta.2003.50100.
6 Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
7 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
8 Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.
9 Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophagesImplications in atherosclerosis. Atherosclerosis. 2006 Oct;188(2):433-43.
10 Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.