Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU0EKLN)

• DOT Name: A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20)
• Synonyms: ADAM-TS 20; ADAM-TS20; ADAMTS-20; EC 3.4.24.-
• Gene Name: ADAMTS20
• Related Disease:
  Cleft lip/palate
  Cleft palate
  Dilated cardiomyopathy 1A
  Hydrocephalus
  Hydrocephalus, nonsyndromic, autosomal recessive 1
  Invasive ductal breast carcinoma
  Isolated cleft palate
  Melanoma
  Neoplasm
  Peters plus syndrome
• UniProt ID: ATS20_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF17771 ; PF19236 ; PF05986 ; PF08685 ; PF01562 ; PF01421 ; PF19030 ; PF00090
• Sequence:
  MWVAKWLTGLLYHLSLFITRSWEVDFHPRQEALVRTLTSYEVVIPERVNEFGEVFPQSHH
  FSRQKRSSEALEPMPFRTHYRFTAYGQLFQLNLTADASFLAAGYTEVHLGTPERGAWESD
  AGPSDLRHCFYRGQVNSQEDYKAVVSLCGGLTGTFKGQNGEYFLEPIMKADGNEYEDGHN
  KPHLIYRQDLNNSFLQTLKYCSVSESQIKETSLPFHTYSNMNEDLNVMKERVLGHTSKNV
  PLKDERRHSRKKRLISYPRYIEIMVTADAKVVSAHGSNLQNYILTLMSIVATIYKDPSIG
  NLIHIVVVKLVMIHREEEGPVINFDGATTLKNFCSWQQTQNDLDDVHPSHHDTAVLITRE
  DICSSKEKCNMLGLSYLGTICDPLQSCFINEEKGLISAFTIAHELGHTLGVQHDDNPRCK
  EMKVTKYHVMAPALSFHMSPWSWSNCSRKYVTEFLDTGYGECLLDKPDEEIYNLPSELPG
  SRYDGNKQCELAFGPGSQMCPHINICMHLWCTSTEKLHKGCFTQHVPPADGTDCGPGMHC
  RHGLCVNKETETRPVNGEWGPWEPYSSCSRTCGGGIESATRRCNRPEPRNGGNYCVGRRM
  KFRSCNTDSCPKGTQDFREKQCSDFNGKHLDISGIPSNVRWLPRYSGIGTKDRCKLYCQV
  AGTNYFYLLKDMVEDGTPCGTETHDICVQGQCMAAGCDHVLNSSAKIDKCGVCGGDNSSC
  KTITGVFNSSHYGYNVVVKIPAGATNVDIRQYSYSGQPDDSYLALSDAEGNFLFNGNFLL
  STSKKEINVQGTRTVIEYSGSNNAVERINSTNRQEKEILIEVLCVGNLYNPDVHYSFNIP
  LEERSDMFTWDPYGPWEGCTKMCQGLQRRNITCIHKSDHSVVSDKECDHLPLPSFVTQSC
  NTDCELRWHVIGKSECSSQCGQGYRTLDIHCMKYSIHEGQTVQVDDHYCGDQLKPPTQEL
  CHGNCVFTRWHYSEWSQCSRSCGGGERSRESYCMNNFGHRLADNECQELSRVTRENCNEF
  SCPSWAASEWSECLVTCGKGTKQRQVWCQLNVDHLSDGFCNSSTKPESLSPCELHTCASW
  QVGPWGPCTTTCGHGYQMRDVKCVNELASAVLEDTECHEASRPSDRQSCVLTPCSFISKL
  ETALLPTVLIKKMAQWRHGSWTPCSVSCGRGTQARYVSCRDALDRIADESYCAHLPRPAE
  IWDCFTPCGEWQAGDWSPCSASCGHGKTTRQVLCMNYHQPIDENYCDPEVRPLMEQECSL
  AACPPAHSHFPSSPVQPSYYLSTNLPLTQKLEDNENQVVHPSVRGNQWRTGPWGSCSSSC
  SGGLQHRAVVCQDENGQSASYCDAASKPPELQQCGPGPCPQWNYGNWGECSQTCGGGIKS
  RLVICQFPNGQILEDHNCEIVNKPPSVIQCHMHACPADVSWHQEPWTSCSASCGKGRKYR
  EVFCIDQFQRKLEDTNCSQVQKPPTHKACRSVRCPSWKANSWNECSVTCGSGVQQRDVYC
  RLKGVGQVVEEMCDQSTRPCSQRRCWSQDCVQHKGMERGRLNCSTSCERKDSHQRMECTD
  NQIRQVNEIVYNSSTISLTSKNCRNPPCNYIVVTADSSQCANNCGFSYRQRITYCTEIPS
  TKKHKLHRLRPIVYQECPVVPSSQVYQCINSCLHLATWKVGKWSKCSVTCGIGIMKRQVK
  CITKHGLSSDLCLNHLKPGAQKKCYANDCKSFTTCKEIQVKNHIRKDGDYYLNIKGRIIK
  IYCADMYLENPKEYLTLVQGEENFSEVYGFRLKNPYQCPFNGSRREDCECDNGHLAAGYT
  VFSKIRIDLTSMQIKTTDLLFSKTIFGNAVPFATAGDCYSAFRCPQGQFSINLSGTGMKI
  SSTAKWLTQGSYTSVSIRRSEDGTRFFGKCGGYCGKCLPHMTTGLPIQVI
• Function: May play a role in tissue-remodeling process occurring in both normal and pathological conditions. May have a protease-independent function in the transport from the endoplasmic reticulum to the Golgi apparatus of secretory cargos, mediated by the GON domain.
• Tissue Specificity: Very sparingly expressed, although is detected at low levels in testis, prostate, ovary, heart, placenta, lung and pancreas. Overexpressed in several brain, colon and breast carcinomas.
• Reactome Pathway:
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Defective B3GALTL causes PpS (R-HSA-5083635)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[1]
Cleft palate	DIS6G5TF	Strong	Biomarker	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[3]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[2]
Hydrocephalus, nonsyndromic, autosomal recessive 1	DISCYZI4	Strong	Genetic Variation	[2]
Invasive ductal breast carcinoma	DIS43J58	Strong	Biomarker	[3]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[3]
Peters plus syndrome	DISIUM7O	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20) increases the Hypersensitivity ADR of Phenytoin.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[8]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Glucosamine	DM4ZLFD	Approved	Glucosamine decreases the cleavage of A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[10]

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 A disintegrin and metalloproteinase with thrombospondin motifs 20 (ADAMTS20).	[12]

References

• [1] Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.PLoS Genet. 2015 Mar 23;11(3):e1005059. doi: 10.1371/journal.pgen.1005059. eCollection 2015 Mar.
• [2] ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome.Hum Mol Genet. 2019 Dec 15;28(24):4053-4066. doi: 10.1093/hmg/ddz225.
• [3] Relationship Between ADAMTS8, ADAMTS18, and ADAMTS20 (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) Expressions and Tumor Molecular Classification, Clinical Pathological Parameters, and Prognosis in Breast Invasive Ductal Carcinoma.Med Sci Monit. 2018 Jun 3;24:3726-3735. doi: 10.12659/MSM.907310.
• [4] A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene.PLoS One. 2011 Apr 29;6(4):e19271. doi: 10.1371/journal.pone.0019271.
• [5] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] 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.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] 10mM glucosamine prevents activation of proADAMTS5 (aggrecanase-2) in transfected cells by interference with post-translational modification of furin. Osteoarthritis Cartilage. 2010 Mar;18(3):455-63. doi: 10.1016/j.joca.2009.10.014. Epub 2009 Nov 4.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.