Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA17R1M)

• DOT Name: Transmembrane protease serine 6 (TMPRSS6)
• Synonyms: EC 3.4.21.-; Matriptase-2
• Gene Name: TMPRSS6
• Related Disease: IRIDA syndrome
• UniProt ID: TMPS6_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF00057 ; PF01390 ; PF00089
• Sequence:
  MLLLFHSKRMPVAEAPQVAGGQGDGGDGEEAEPEGMFKACEDSKRKARGYLRLVPLFVLL
  ALLVLASAGVLLWYFLGYKAEVMVSQVYSGSLRVLNRHFSQDLTRRESSAFRSETAKAQK
  MLKELITSTRLGTYYNSSSVYSFGEGPLTCFFWFILQIPEHRRLMLSPEVVQALLVEELL
  STVNSSAAVPYRAEYEVDPEGLVILEASVKDIAALNSTLGCYRYSYVGQGQVLRLKGPDH
  LASSCLWHLQGPKDLMLKLRLEWTLAECRDRLAMYDVAGPLEKRLITSVYGCSRQEPVVE
  VLASGAIMAVVWKKGLHSYYDPFVLSVQPVVFQACEVNLTLDNRLDSQGVLSTPYFPSYY
  SPQTHCSWHLTVPSLDYGLALWFDAYALRRQKYDLPCTQGQWTIQNRRLCGLRILQPYAE
  RIPVVATAGITINFTSQISLTGPGVRVHYGLYNQSDPCPGEFLCSVNGLCVPACDGVKDC
  PNGLDERNCVCRATFQCKEDSTCISLPKVCDGQPDCLNGSDEEQCQEGVPCGTFTFQCED
  RSCVKKPNPQCDGRPDCRDGSDEEHCDCGLQGPSSRIVGGAVSSEGEWPWQASLQVRGRH
  ICGGALIADRWVITAAHCFQEDSMASTVLWTVFLGKVWQNSRWPGEVSFKVSRLLLHPYH
  EEDSHDYDVALLQLDHPVVRSAAVRPVCLPARSHFFEPGLHCWITGWGALREGGPISNAL
  QKVDVQLIPQDLCSEVYRYQVTPRMLCAGYRKGKKDACQGDSGGPLVCKALSGRWFLAGL
  VSWGLGCGRPNYFGVYTRITGVISWIQQVVT
• Function: Membrane-bound serine protease. Through the cleavage of cell surface HJV, a regulator of the expression of the iron absorption-regulating hormone hepicidin/HAMP, plays a role in iron homeostasis.
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
IRIDA syndrome	DISPN8YW	Definitive	Autosomal recessive	[1]

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 Transmembrane protease serine 6 (TMPRSS6).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane protease serine 6 (TMPRSS6).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of Transmembrane protease serine 6 (TMPRSS6).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transmembrane protease serine 6 (TMPRSS6).	[5]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Transmembrane protease serine 6 (TMPRSS6).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Transmembrane protease serine 6 (TMPRSS6).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane protease serine 6 (TMPRSS6).	[8]

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 increases the methylation of Transmembrane protease serine 6 (TMPRSS6).	[7]

References

• [1] Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008 May;40(5):569-71. doi: 10.1038/ng.130. Epub 2008 Apr 13.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [7] 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.
• [8] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.