Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFJ1PDB)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14)
• Synonyms: ADAM-TS 14; ADAM-TS14; ADAMTS-14; EC 3.4.24.-
• Gene Name: ADAMTS14
• Related Disease:
  Knee osteoarthritis
  Colorectal carcinoma
  Neoplasm
  Oral cancer
  Osteoarthritis
  Hepatocellular carcinoma
  Multiple sclerosis
  Asthma
• UniProt ID: ATS14_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MAPLRALLSYLLPLHCALCAAAGSRTPELHLSGKLSDYGVTVPCSTDFRGRFLSHVVSGP
  AAASAGSMVVDTPPTLPRHSSHLRVARSPLHPGGTLWPGRVGRHSLYFNVTVFGKELHLR
  LRPNRRLVVPGSSVEWQEDFRELFRQPLRQECVYTGGVTGMPGAAVAISNCDGLAGLIRT
  DSTDFFIEPLERGQQEKEASGRTHVVYRREAVQQEWAEPDGDLHNEAFGLGDLPNLLGLV
  GDQLGDTERKRRHAKPGSYSIEVLLVVDDSVVRFHGKEHVQNYVLTLMNIVDEIYHDESL
  GVHINIALVRLIMVGYRQSLSLIERGNPSRSLEQVCRWAHSQQRQDPSHAEHHDHVVFLT
  RQDFGPSGYAPVTGMCHPLRSCALNHEDGFSSAFVIAHETGHVLGMEHDGQGNGCADETS
  LGSVMAPLVQAAFHRFHWSRCSKLELSRYLPSYDCLLDDPFDPAWPQPPELPGINYSMDE
  QCRFDFGSGYQTCLAFRTFEPCKQLWCSHPDNPYFCKTKKGPPLDGTECAPGKWCFKGHC
  IWKSPEQTYGQDGGWSSWTKFGSCSRSCGGGVRSRSRSCNNPSPAYGGRLCLGPMFEYQV
  CNSEECPGTYEDFRAQQCAKRNSYYVHQNAKHSWVPYEPDDDAQKCELICQSADTGDVVF
  MNQVVHDGTRCSYRDPYSVCARGECVPVGCDKEVGSMKADDKCGVCGGDNSHCRTVKGTL
  GKASKQAGALKLVQIPAGARHIQIEALEKSPHRIVVKNQVTGSFILNPKGKEATSRTFTA
  MGLEWEDAVEDAKESLKTSGPLPEAIAILALPPTEGGPRSSLAYKYVIHEDLLPLIGSNN
  VLLEEMDTYEWALKSWAPCSKACGGGIQFTKYGCRRRRDHHMVQRHLCDHKKRPKPIRRR
  CNQHPCSQPVWVTEEWGACSRSCGKLGVQTRGIQCLLPLSNGTHKVMPAKACAGDRPEAR
  RPCLRVPCPAQWRLGAWSQCSATCGEGIQQRQVVCRTNANSLGHCEGDRPDTVQVCSLPA
  CGGNHQNSTVRADVWELGTPEGQWVPQSEPLHPINKISSTEPCTGDRSVFCQMEVLDRYC
  SIPGYHRLCCVSCIKKASGPNPGPDPGPTSLPPFSTPGSPLPGPQDPADAAEPPGKPTGS
  EDHQHGRATQLPGALDTSSPGTQHPFAPETPIPGASWSISPTTPGGLPWGWTQTPTPVPE
  DKGQPGEDLRHPGTSLPAASPVT
• Function: Has aminoprocollagen type I processing activity in the absence of ADAMTS2. Seems to be synthesized as a latent enzyme that requires activation to display aminoprocollagen peptidase activity. Cleaves lysyl oxidase LOX at a site downstream of its propeptide cleavage site to produce a short LOX form.
• Tissue Specificity: Expressed in retina and at low levels in brain, lung and placenta . High expression in fetal tissues .
• Reactome Pathway:
  Defective B3GALTL causes PpS (R-HSA-5083635)
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Knee osteoarthritis	DISLSNBJ	Definitive	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Oral cancer	DISLD42D	Strong	Genetic Variation	[4]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Disputed	Biomarker	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 14 (ADAMTS14).	[9]

References

• [1] Relationship between ADAMTS14/rs4747096 gene polymorphism and knee osteoarthritis in Chinese population.Biosci Rep. 2018 Oct 22;38(5):BSR20181413. doi: 10.1042/BSR20181413. Print 2018 Oct 31.
• [2] Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.Oncotarget. 2015 Feb 20;6(5):3420-31. doi: 10.18632/oncotarget.2852.
• [3] The competing endogenous circular RNA ADAMTS14 suppressed hepatocellular carcinoma progression through regulating microRNA-572/regulator of calcineurin 1.J Cell Physiol. 2019 Mar;234(3):2460-2470. doi: 10.1002/jcp.26764. Epub 2018 Oct 14.
• [4] ADAMTS14 Gene Polymorphism and Environmental Risk in the Development of Oral Cancer.PLoS One. 2016 Jul 27;11(7):e0159585. doi: 10.1371/journal.pone.0159585. eCollection 2016.
• [5] ADAMTS14 gene polymorphism associated with knee osteoarthritis in Thai women.Genet Mol Res. 2013 Nov 7;12(4):5301-9. doi: 10.4238/2013.November.7.5.
• [6] Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis.J Neuroimmunol. 2005 Jul;164(1-2):140-7. doi: 10.1016/j.jneuroim.2005.04.005.
• [7] Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases.J Allergy Clin Immunol. 2012 Oct;130(4):861-8.e7. doi: 10.1016/j.jaci.2012.04.041. Epub 2012 Jun 12.
• [8] 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.
• [9] 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.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.