Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTM6KRB)

• DOT Name: Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17)
• Synonyms: ADAM 17; EC 3.4.24.86; Snake venom-like protease; TNF-alpha convertase; TNF-alpha-converting enzyme; CD antigen CD156b
• Gene Name: ADAM17
• Related Disease:
  Inflammatory skin and bowel disease, neonatal, 1
  Neonatal inflammatory skin and bowel disease
  Congenital heart disease
• UniProt ID: ADA17_HUMAN
• PDB ID: 1BKC; 1ZXC; 2A8H; 2DDF; 2FV5; 2FV9; 2I47; 2M2F; 2OI0; 3B92; 3CKI; 3E8R; 3EDZ; 3EWJ; 3G42; 3KMC; 3KME; 3L0T; 3L0V; 3LE9; 3LEA; 3LGP; 3O64; 8CQY
• EC Number: 3.4.24.86
• Pfam ID: PF16698 ; PF00200 ; PF13574
• Sequence:
  MRQSLLFLTSVVPFVLAPRPPDDPGFGPHQRLEKLDSLLSDYDILSLSNIQQHSVRKRDL
  QTSTHVETLLTFSALKRHFKLYLTSSTERFSQNFKVVVVDGKNESEYTVKWQDFFTGHVV
  GEPDSRVLAHIRDDDVIIRINTDGAEYNIEPLWRFVNDTKDKRMLVYKSEDIKNVSRLQS
  PKVCGYLKVDNEELLPKGLVDREPPEELVHRVKRRADPDPMKNTCKLLVVADHRFYRYMG
  RGEESTTTNYLIELIDRVDDIYRNTSWDNAGFKGYGIQIEQIRILKSPQEVKPGEKHYNM
  AKSYPNEEKDAWDVKMLLEQFSFDIAEEASKVCLAHLFTYQDFDMGTLGLAYVGSPRANS
  HGGVCPKAYYSPVGKKNIYLNSGLTSTKNYGKTILTKEADLVTTHELGHNFGAEHDPDGL
  AECAPNEDQGGKYVMYPIAVSGDHENNKMFSNCSKQSIYKTIESKAQECFQERSNKVCGN
  SRVDEGEECDPGIMYLNNDTCCNSDCTLKEGVQCSDRNSPCCKNCQFETAQKKCQEAINA
  TCKGVSYCTGNSSECPPPGNAEDDTVCLDLGKCKDGKCIPFCEREQQLESCACNETDNSC
  KVCCRDLSGRCVPYVDAEQKNLFLRKGKPCTVGFCDMNGKCEKRVQDVIERFWDFIDQLS
  INTFGKFLADNIVGSVLVFSLIFWIPFSILVHCVDKKLDKQYESLSLFHPSNVEMLSSMD
  SASVRIIKPFPAPQTPGRLQPAPVIPSAPAAPKLDHQRMDTIQEDPSTDSHMDEDGFEKD
  PFPNSSTAAKSFEDLTDHPVTRSEKAASFKLQRQNRVDSKETEC
• Function: Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein. Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT). Plays a role in the proteolytic processing of ACE2. Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain. Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3. Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R. Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells.
• Tissue Specificity: Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. Expressed in natural killer cells (at protein level) .
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Notch sig.ling pathway (hsa04330)
  TNF sig.ling pathway (hsa04668)
  Alzheimer disease (hsa05010)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Collagen degradation (R-HSA-1442490)
  Signaling by EGFR (R-HSA-177929)
  Regulated proteolysis of p75NTR (R-HSA-193692)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Release of Hh-Np from the secreting cell (R-HSA-5362798)
  TNF signaling (R-HSA-75893)
  CD163 mediating an anti-inflammatory response (R-HSA-9662834)
  Growth hormone receptor signaling (R-HSA-982772)
  M1580_K2555) Translocation Mutant (9)(NOTCH1)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory skin and bowel disease, neonatal, 1	DISLZ6AP	Strong	Autosomal recessive	[1]
Neonatal inflammatory skin and bowel disease	DISMIIM2	Supportive	Autosomal recessive	[2]
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[3]

26 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 Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the activity of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[13]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[15]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[17]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[18]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[25]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[26]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[27]
U0126	DM31OGF	Investigative	U0126 increases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[13]
Cordycepin	DM72Y01	Investigative	Cordycepin decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[16]
ROSMARINIC ACID	DMQ6SJT	Investigative	ROSMARINIC ACID decreases the expression of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[18]

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 Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the stability of Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17).	[16]

References

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• [18] Rosmarinic acid down-regulates endothelial protein C receptor shedding in vitro and in vivo. Food Chem Toxicol. 2013 Sep;59:311-5. doi: 10.1016/j.fct.2013.06.003. Epub 2013 Jun 14.
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• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
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