Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2U6VF5)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3)
• Synonyms: ADAM-TS 3; ADAM-TS3; ADAMTS-3; EC 3.4.24.-; Procollagen II N-proteinase; PC II-NP; Procollagen II amino propeptide-processing enzyme
• Gene Name: ADAMTS3
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Chondrosarcoma
  Dental caries
  Ehlers-Danlos syndrome, dermatosparaxis type
  Hennekam lymphangiectasia-lymphedema syndrome 3
  Intervertebral disc degeneration
  Knee osteoarthritis
  Lhermitte-Duclos disease
  Obstructive lung disease
  Osteoarthritis
  Osteosarcoma
  Schizophrenia
  Sleep apnea syndrome
  Tendinopathy
  Alzheimer disease
  Colorectal carcinoma
  Laryngeal squamous cell carcinoma
  Hennekam syndrome
  Multiple sclerosis
  Tuberculosis
  Amyotrophic lateral sclerosis
  Arthritis
  Cone-rod dystrophy 2
  Rheumatoid arthritis
  Type-1 diabetes
• UniProt ID: ATS3_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MVLLSLWLIAAALVEVRTSADGQAGNEEMVQIDLPIKRYREYELVTPVSTNLEGRYLSHT
  LSASHKKRSARDVSSNPEQLFFNITAFGKDFHLRLKPNTQLVAPGAVVEWHETSLVPGNI
  TDPINNHQPGSATYRIRRTEPLQTNCAYVGDIVDIPGTSVAISNCDGLAGMIKSDNEEYF
  IEPLERGKQMEEEKGRIHVVYKRSAVEQAPIDMSKDFHYRESDLEGLDDLGTVYGNIHQQ
  LNETMRRRRHAGENDYNIEVLLGVDDSVVRFHGKEHVQNYLLTLMNIVNEIYHDESLGVH
  INVVLVRMIMLGYAKSISLIERGNPSRSLENVCRWASQQQRSDLNHSEHHDHAIFLTRQD
  FGPAGMQGYAPVTGMCHPVRSCTLNHEDGFSSAFVVAHETGHVLGMEHDGQGNRCGDETA
  MGSVMAPLVQAAFHRYHWSRCSGQELKRYIHSYDCLLDDPFDHDWPKLPELPGINYSMDE
  QCRFDFGVGYKMCTAFRTFDPCKQLWCSHPDNPYFCKTKKGPPLDGTECAAGKWCYKGHC
  MWKNANQQKQDGNWGSWTKFGSCSRTCGTGVRFRTRQCNNPMPINGGQDCPGVNFEYQLC
  NTEECQKHFEDFRAQQCQQRNSHFEYQNTKHHWLPYEHPDPKKRCHLYCQSKETGDVAYM
  KQLVHDGTHCSYKDPYSICVRGECVKVGCDKEIGSNKVEDKCGVCGGDNSHCRTVKGTFT
  RTPRKLGYLKMFDIPPGARHVLIQEDEASPHILAIKNQATGHYILNGKGEEAKSRTFIDL
  GVEWDYNIEDDIESLHTDGPLHDPVIVLIIPQENDTRSSLTYKYIIHEDSVPTINSNNVI
  QEELDTFEWALKSWSQCSKPCGGGFQYTKYGCRRKSDNKMVHRSFCEANKKPKPIRRMCN
  IQECTHPLWVAEEWEHCTKTCGSSGYQLRTVRCLQPLLDGTNRSVHSKYCMGDRPESRRP
  CNRVPCPAQWKTGPWSECSVTCGEGTEVRQVLCRAGDHCDGEKPESVRACQLPPCNDEPC
  LGDKSIFCQMEVLARYCSIPGYNKLCCESCSKRSSTLPPPYLLEAAETHDDVISNPSDLP
  RSLVMPTSLVPYHSETPAKKMSLSSISSVGGPNAYAAFRPNSKPDGANLRQRSAQQAGSK
  TVRLVTVPSSPPTKRVHLSSASQMAAASFFAASDSIGASSQARTSKKDGKIIDNRRPTRS
  STLER
• Function: Cleaves the propeptides of type II collagen prior to fibril assembly. Does not act on types I and III collagens.
• Tissue Specificity: Found in cartilage and skin.
• 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

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[1]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[4]
Dental caries	DISRBCMD	Strong	Genetic Variation	[5]
Ehlers-Danlos syndrome, dermatosparaxis type	DISRDFCX	Strong	Biomarker	[4]
Hennekam lymphangiectasia-lymphedema syndrome 3	DISSMZWA	Strong	Autosomal recessive	[6]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[7]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[8]
Lhermitte-Duclos disease	DIS87XW7	Strong	Genetic Variation	[9]
Obstructive lung disease	DIS4IIDZ	Strong	Biomarker	[10]
Osteoarthritis	DIS05URM	Strong	Biomarker	[11]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[12]
Sleep apnea syndrome	DISER6KS	Strong	Biomarker	[13]
Tendinopathy	DISJH7UX	Strong	Biomarker	[14]
Alzheimer disease	DISF8S70	moderate	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[16]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[17]
Hennekam syndrome	DISIQGJQ	Supportive	Autosomal recessive	[18]
Multiple sclerosis	DISB2WZI	Disputed	Biomarker	[19]
Tuberculosis	DIS2YIMD	Disputed	Altered Expression	[20]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[15]
Arthritis	DIST1YEL	Limited	Biomarker	[15]
Cone-rod dystrophy 2	DISX2RWY	Limited	Biomarker	[15]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[21]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[22]

10 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 A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[26]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[27]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of A disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3).	[31]

References

• [1] The expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 in human macrophages is inhibited by the anti-atherogenic cytokine transforming growth factor- and requires Smads, p38 mitogen-activated protein kinase and c-Jun.Int J Biochem Cell Biol. 2011 May;43(5):805-11. doi: 10.1016/j.biocel.2011.02.005. Epub 2011 Feb 18.
• [2] SP1-mediated downregulation of ADAMTS3 gene expression in osteosarcoma models.Gene. 2018 Jun 15;659:1-10. doi: 10.1016/j.gene.2018.03.009. Epub 2018 Mar 5.
• [3] Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells.Oncotarget. 2017 Feb 21;8(8):13716-13729. doi: 10.18632/oncotarget.14627.
• [4] Procollagen II amino propeptide processing by ADAMTS-3. Insights on dermatosparaxis.J Biol Chem. 2001 Aug 24;276(34):31502-9. doi: 10.1074/jbc.M103466200. Epub 2001 Jun 14.
• [5] Genome-wide association scan of dental caries in the permanent dentition.BMC Oral Health. 2012 Dec 21;12:57. doi: 10.1186/1472-6831-12-57.
• [6] ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis. Angiogenesis. 2016 Jan;19(1):53-65. doi: 10.1007/s10456-015-9488-z. Epub 2015 Oct 7.
• [7] Elevated expression of hypoxia-inducible factor-2alpha regulated catabolic factors during intervertebral disc degeneration.Life Sci. 2019 Sep 1;232:116565. doi: 10.1016/j.lfs.2019.116565. Epub 2019 Jun 26.
• [8] Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages.Genet Mol Res. 2014 Nov 14;13(4):9642-9. doi: 10.4238/2014.November.14.9.
• [9] Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population.J Orthop Res. 2016 May;34(5):860-4. doi: 10.1002/jor.23081. Epub 2015 Nov 23.
• [10] An ADAMTS3 missense variant is associated with Norwich Terrier upper airway syndrome.PLoS Genet. 2019 May 16;15(5):e1008102. doi: 10.1371/journal.pgen.1008102. eCollection 2019 May.
• [11] Purification and Activity Determination of ADAMTS-4 and ADAMTS-5 and Their Domain Deleted Mutants.Methods Mol Biol. 2020;2043:75-91. doi: 10.1007/978-1-4939-9698-8_7.
• [12] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [13] Association between the ADAMTS proteinases and obstructive sleep apnea.Sleep Breath. 2020 Sep;24(3):835-840. doi: 10.1007/s11325-019-01909-0. Epub 2019 Aug 16.
• [14] The regulation of aggrecanase ADAMTS-4 expression in human Achilles tendon and tendon-derived cells.Matrix Biol. 2008 Jun;27(5):393-401. doi: 10.1016/j.matbio.2008.02.002. Epub 2008 Apr 2.
• [15] ADAMTS-4 in central nervous system pathologies.J Neurosci Res. 2017 Sep;95(9):1703-1711. doi: 10.1002/jnr.24021. Epub 2017 Jan 13.
• [16] Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages.Cell Physiol Biochem. 2018;46(4):1693-1703. doi: 10.1159/000489245. Epub 2018 Apr 20.
• [17] Expression and distribution of aggrecanases in human larynx: ADAMTS-5/aggrecanase-2 is the main aggrecanase in laryngeal carcinoma.Biochimie. 2013 Apr;95(4):725-34. doi: 10.1016/j.biochi.2012.10.022. Epub 2012 Nov 3.
• [18] Loss of ADAMTS3 activity causes Hennekam lymphangiectasia-lymphedema syndrome 3. Hum Mol Genet. 2017 Nov 1;26(21):4095-4104. doi: 10.1093/hmg/ddx297.
• [19] Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter.Mult Scler. 2006 Aug;12(4):386-96. doi: 10.1191/135248506ms1300oa.
• [20] Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with tuberculous intervertebral discs and healthy controls.Clin Biochem. 2013 May;46(7-8):603-11. doi: 10.1016/j.clinbiochem.2013.02.006. Epub 2013 Feb 26.
• [21] Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.Arthritis Rheumatol. 2015 Jun;67(6):1481-90. doi: 10.1002/art.39086.
• [22] Leptin downregulates aggrecan through the p38-ADAMST pathway in human nucleus pulposus cells.PLoS One. 2014 Oct 9;9(10):e109595. doi: 10.1371/journal.pone.0109595. eCollection 2014.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [25] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [26] 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.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] 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.
• [29] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [30] 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.
• [31] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.