Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWSZ0QT)

• DOT Name: Leukotriene A-4 hydrolase (LTA4H)
• Synonyms: LTA-4 hydrolase; EC 3.3.2.6; Leukotriene A(4) hydrolase; Tripeptide aminopeptidase LTA4H; EC 3.4.11.4
• Gene Name: LTA4H
• UniProt ID: LKHA4_HUMAN
• PDB ID: 1GW6 ; 1H19 ; 1HS6 ; 1SQM ; 2R59 ; 2VJ8 ; 3B7R ; 3B7S ; 3B7T ; 3B7U ; 3CHO ; 3CHP ; 3CHQ ; 3CHR ; 3CHS ; 3FH5 ; 3FH7 ; 3FH8 ; 3FHE ; 3FTS ; 3FTU ; 3FTV ; 3FTW ; 3FTX ; 3FTY ; 3FTZ ; 3FU0 ; 3FU3 ; 3FU5 ; 3FU6 ; 3FUD ; 3FUE ; 3FUF ; 3FUH ; 3FUI ; 3FUJ ; 3FUK ; 3FUL ; 3FUM ; 3FUN ; 3U9W ; 4DPR ; 4L2L ; 4MKT ; 4MS6 ; 4R7L ; 4RSY ; 4RVB ; 5AEN ; 5BPP ; 5FWQ ; 5N3W ; 5NI2 ; 5NI4 ; 5NI6 ; 5NIA ; 5NID ; 5NIE ; 6ENB ; 6ENC ; 6END ; 6O5H ; 7AUZ ; 7AV0 ; 7AV1 ; 7AV2 ; 7KZE ; 7LLQ ; 8AVA ; 8AWH ; 8QOW ; 8QPN ; 8QQ4
• EC Number: 3.3.2.6; 3.4.11.4
• Pfam ID: PF09127 ; PF01433 ; PF17900
• Sequence:
  MPEIVDTCSLASPASVCRTKHLHLRCSVDFTRRTLTGTAALTVQSQEDNLRSLVLDTKDL
  TIEKVVINGQEVKYALGERQSYKGSPMEISLPIALSKNQEIVIEISFETSPKSSALQWLT
  PEQTSGKEHPYLFSQCQAIHCRAILPCQDTPSVKLTYTAEVSVPKELVALMSAIRDGETP
  DPEDPSRKIYKFIQKVPIPCYLIALVVGALESRQIGPRTLVWSEKEQVEKSAYEFSETES
  MLKIAEDLGGPYVWGQYDLLVLPPSFPYGGMENPCLTFVTPTLLAGDKSLSNVIAHEISH
  SWTGNLVTNKTWDHFWLNEGHTVYLERHICGRLFGEKFRHFNALGGWGELQNSVKTFGET
  HPFTKLVVDLTDIDPDVAYSSVPYEKGFALLFYLEQLLGGPEIFLGFLKAYVEKFSYKSI
  TTDDWKDFLYSYFKDKVDVLNQVDWNAWLYSPGLPPIKPNYDMTLTNACIALSQRWITAK
  EDDLNSFNATDLKDLSSHQLNEFLAQTLQRAPLPLGHIKRMQEVYNFNAINNSEIRFRWL
  RLCIQSKWEDAIPLALKMATEQGRMKFTRPLFKDLAAFDKSHDQAVRTYQEHKASMHPVT
  AMLVGKDLKVD
• Function: Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides. In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Biosynthesis of D-series resolvins (R-HSA-9018676)
  Biosynthesis of protectins (R-HSA-9018681)
  Biosynthesis of E-series 18(S)-resolvins (R-HSA-9018896)
  Biosynthesis of aspirin-triggered D-series resolvins (R-HSA-9020265)
  Biosynthesis of E-series 18(R)-resolvins (R-HSA-9023661)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
• BioCyc Pathway: MetaCyc:HS03372-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Leukotriene A-4 hydrolase (LTA4H) decreases the response to substance of Arsenic trioxide.	[21]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LTB4	DME26RS	Phase 2	Leukotriene A-4 hydrolase (LTA4H) increases the chemical synthesis of LTB4.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leukotriene A-4 hydrolase (LTA4H).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Leukotriene A-4 hydrolase (LTA4H).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Leukotriene A-4 hydrolase (LTA4H).	[13]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Leukotriene A-4 hydrolase (LTA4H).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Leukotriene A-4 hydrolase (LTA4H).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Leukotriene A-4 hydrolase (LTA4H).	[20]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [21] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [22] Anti-inflammatory activity of a potent, selective leukotriene A4 hydrolase inhibitor in comparison with the 5-lipoxygenase inhibitor zileuton. J Pharmacol Exp Ther. 2007 Jun;321(3):1154-60. doi: 10.1124/jpet.106.115436. Epub 2007 Mar 19.