Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFMZ8I2)

• DOT Name: Multiple C2 and transmembrane domain-containing protein 2 (MCTP2)
• Gene Name: MCTP2
• Related Disease:
  Aorta coarctation
  Chronic renal failure
  Diabetic retinopathy
  End-stage renal disease
  Hypoplastic left heart syndrome 1
  Major depressive disorder
  Obesity
  Schizophrenia
• UniProt ID: MCTP2_HUMAN
• PDB ID: 2EP6
• Pfam ID: PF00168 ; PF08372
• Sequence:
  MDLDKPSVWGSLKQRTRPLLINLSKKKVKKNPSKPPDLRARHHLDRRLSLSVPDLLEAEA
  LAPEGRPYSGPQSSYTSVPSSLSTAGIFPKSSSSSLKQSEEELDWSQEEASHLHVVETDS
  EEAYASPAERRRVSSNGIFDLQKTSLGGDAPEEPEKLCGSSDLNASMTSQHFEEQSVPGE
  ASDGLSNLPSPFAYLLTIHLKEGRNLVVRDRCGTSDPYVKFKLNGKTLYKSKVIYKNLNP
  VWDEIVVLPIQSLDQKLRVKVYDRDLTTSDFMGSAFVILSDLELNRTTEHILKLEDPNSL
  EDDMGVIVLNLNLVVKQGDFKRHRWSNRKRLSASKSSLIRNLRLSESLKKNQLWNGIISI
  TLLEGKNVSGGSMTEMFVQLKLGDQRYKSKTLCKSANPQWQEQFDFHYFSDRMGILDIEV
  WGKDNKKHEERLGTCKVDISALPLKQANCLELPLDSCLGALLMLVTLTPCAGVSVSDLCV
  CPLADLSERKQITQRYCLQNSLKDVKDVGILQVKVLKAADLLAADFSGKSDPFCLLELGN
  DRLQTHTVYKNLNPEWNKVFTFPIKDIHDVLEVTVFDEDGDKPPDFLGKVAIPLLSIRDG
  QPNCYVLKNKDLEQAFKGVIYLEMDLIYNPVKASIRTFTPREKRFVEDSRKLSKKILSRD
  VDRVKRITMAIWNTMQFLKSCFQWESTLRSTIAFAVFLITVWNFELYMIPLALLLIFVYN
  FIRPVKGKVSSIQDSQESTDIDDEEDEDDKESEKKGLIERIYMVQDIVSTVQNVLEEIAS
  FGERIKNTFNWTVPFLSSLACLILAAATIILYFIPLRYIILIWGINKFTKKLRNPYSIDN
  NELLDFLSRVPSDVQKVQYAELKLCSSHSPLRKKRSAL
• Function: Might play a role in the development of cardiac outflow tract.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aorta coarctation	DISAFXDJ	Strong	Biomarker	[1]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[2]
Diabetic retinopathy	DISHGUJM	Strong	Biomarker	[3]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[2]
Hypoplastic left heart syndrome 1	DISW3OY8	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Multiple C2 and transmembrane domain-containing protein 2 (MCTP2) affects the response to substance of Topotecan.	[21]
Flucloxacillin	DMNUWST	Approved	Multiple C2 and transmembrane domain-containing protein 2 (MCTP2) increases the Liver injury ADR of Flucloxacillin.	[22]

12 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 Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[20]

2 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 Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Multiple C2 and transmembrane domain-containing protein 2 (MCTP2).	[15]

References

• [1] MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.Hum Mol Genet. 2013 Nov 1;22(21):4339-48. doi: 10.1093/hmg/ddt283. Epub 2013 Jun 16.
• [2] Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.Diabetologia. 2014 Aug;57(8):1611-22. doi: 10.1007/s00125-014-3256-2. Epub 2014 May 29.
• [3] Progress in Defining the Genetic Basis of Diabetic Complications.Curr Diab Rep. 2017 Sep;17(9):80. doi: 10.1007/s11892-017-0906-z.
• [4] Linkage disequilibrium mapping of a chromosome 15q25-26 major depression linkage region and sequencing of NTRK3.Biol Psychiatry. 2008 Jun 15;63(12):1185-9. doi: 10.1016/j.biopsych.2008.02.005. Epub 2008 Mar 25.
• [5] Evidence of linkage and association with body fatness and abdominal fat on chromosome 15q26.Obesity (Silver Spring). 2007 Aug;15(8):2061-70. doi: 10.1038/oby.2007.245.
• [6] Association of MCTP2 gene variants with schizophrenia in three independent samples of Scandinavian origin (SCOPE).Psychiatry Res. 2009 Aug 15;168(3):256-8. doi: 10.1016/j.psychres.2008.08.007. Epub 2009 Feb 15.
• [7] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [22] HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009 Jul;41(7):816-9. doi: 10.1038/ng.379. Epub 2009 May 31.