Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRT46B5)

• DOT Name: Lysyl oxidase homolog 2 (LOXL2)
• Synonyms: EC 1.4.3.13; Lysyl oxidase-like protein 2; Lysyl oxidase-related protein 2; Lysyl oxidase-related protein WS9-14
• Gene Name: LOXL2
• UniProt ID: LOXL2_HUMAN
• PDB ID: 5ZE3
• EC Number: 1.4.3.13
• Pfam ID: PF01186 ; PF00530
• Sequence:
  MERPLCSHLCSCLAMLALLSPLSLAQYDSWPHYPEYFQQPAPEYHQPQAPANVAKIQLRL
  AGQKRKHSEGRVEVYYDGQWGTVCDDDFSIHAAHVVCRELGYVEAKSWTASSSYGKGEGP
  IWLDNLHCTGNEATLAACTSNGWGVTDCKHTEDVGVVCSDKRIPGFKFDNSLINQIENLN
  IQVEDIRIRAILSTYRKRTPVMEGYVEVKEGKTWKQICDKHWTAKNSRVVCGMFGFPGER
  TYNTKVYKMFASRRKQRYWPFSMDCTGTEAHISSCKLGPQVSLDPMKNVTCENGLPAVVS
  CVPGQVFSPDGPSRFRKAYKPEQPLVRLRGGAYIGEGRVEVLKNGEWGTVCDDKWDLVSA
  SVVCRELGFGSAKEAVTGSRLGQGIGPIHLNEIQCTGNEKSIIDCKFNAESQGCNHEEDA
  GVRCNTPAMGLQKKLRLNGGRNPYEGRVEVLVERNGSLVWGMVCGQNWGIVEAMVVCRQL
  GLGFASNAFQETWYWHGDVNSNKVVMSGVKCSGTELSLAHCRHDGEDVACPQGGVQYGAG
  VACSETAPDLVLNAEMVQQTTYLEDRPMFMLQCAMEENCLSASAAQTDPTTGYRRLLRFS
  SQIHNNGQSDFRPKNGRHAWIWHDCHRHYHSMEVFTHYDLLNLNGTKVAEGHKASFCLED
  TECEGDIQKNYECANFGDQGITMGCWDMYRHDIDCQWVDITDVPPGDYLFQVVINPNFEV
  AESDYSNNIMKCRSRYDGHRIWMYNCHIGGSFSEETEKKFEHFSGLLNNQLSPQ
• Function: Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation. Shows no activity against histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27' (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated (H3K4me2). Also mediates deamination of methylated TAF10, a member of the transcription factor IID (TFIID) complex, which induces release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription. LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2. Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin CDH1, probably by mediating deamination of histone H3. During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription. SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits. Interacts with the endoplasmic reticulum protein HSPA5 which activates the IRE1-XBP1 pathway of the unfolded protein response, leading to expression of several transcription factors involved in EMT and subsequent EMT induction. Involved in E-cadherin repression following hypoxia, a hallmark of EMT believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression. When secreted into the extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin. Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding. Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation.
• Tissue Specificity: Expressed in many tissues . Highest expression in reproductive tissues, placenta, uterus and prostate . In esophageal epithelium, expressed in the basal, prickle and granular cell layers . Up-regulated in a number of cancers cells and tissues.
• Reactome Pathway:
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Elastic fibre formation (R-HSA-1566948)

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
Topotecan	DMP6G8T	Approved	Lysyl oxidase homolog 2 (LOXL2) affects the response to substance of Topotecan.	[23]

24 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 Lysyl oxidase homolog 2 (LOXL2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Lysyl oxidase homolog 2 (LOXL2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[15]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Lysyl oxidase homolog 2 (LOXL2).	[16]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[17]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Lysyl oxidase homolog 2 (LOXL2).	[18]
Penicillamine	DM40EF6	Approved	Penicillamine decreases the activity of Lysyl oxidase homolog 2 (LOXL2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[22]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[21]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Lysyl oxidase homolog 2 (LOXL2).	[21]

References

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• [7] 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.
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• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
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• [12] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] 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.
• [15] Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Lett. 2005 Jul 4;579(17):3651-9. doi: 10.1016/j.febslet.2005.05.056.
• [16] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [17] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [18] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [19] Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005 Sep;43(3):499-507. doi: 10.1016/j.jhep.2005.02.052.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.