Details of Drug Off-Target (DOT)

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

• DOT Name: Myocardial zonula adherens protein (MYZAP)
• Synonyms: GRINL1A upstream protein; Gup
• Gene Name: MYZAP
• Related Disease:
  Atrial fibrillation
  DiGeorge syndrome
  Juvenile idiopathic arthritis
  Velocardiofacial syndrome
  Arrhythmia
• UniProt ID: MYZAP_HUMAN
• PDB ID: 2KXS
• Sequence:
  MLRSTSTVTLLSGGAARTPGAPSRRANVCRLRLTVPPESPVPEQCEKKIERKEQLLDLSN
  GEPTRKLPQGVVYGVVRRSDQNQQKEMVVYGWSTSQLKEEMNYIKDVRATLEKVRKRMYG
  DYDEMRQKIRQLTQELSVSHAQQEYLENHIQTQSSALDRFNAMNSALASDSIGLQKTLVD
  VTLENSNIKDQIRNLQQTYEASMDKLREKQRQLEVAQVENQLLKMKVESSQEANAEVMRE
  MTKKLYSQYEEKLQEEQRKHSAEKEALLEETNSFLKAIEEANKKMQAAEISLEEKDQRIG
  ELDRLIERMEKERHQLQLQLLEHETEMSGELTDSDKERYQQLEEASASLRERIRHLDDMV
  HCQQKKVKQMVEEIESLKKKLQQKQLLILQLLEKISFLEGENNELQSRLDYLTETQAKTE
  VETREIGVGCDLLPSQTGRTREIVMPSRNYTPYTRVLELTMKKTLT
• Function: Plays a role in cellular signaling via Rho-related GTP-binding proteins and subsequent activation of transcription factor SRF. Targets TJP1 to cell junctions. In cortical neurons, may play a role in glutaminergic signal transduction through interaction with the NMDA receptor subunit GRIN1.
• Tissue Specificity: Detected in heart, liver, skeletal muscle, placenta, small intestine, lung, prostate and testis. Expressed in arrector pili muscle (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[2]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[3]
Velocardiofacial syndrome	DISOSBTY	Strong	Biomarker	[2]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[4]

15 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 Myocardial zonula adherens protein (MYZAP).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Myocardial zonula adherens protein (MYZAP).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Myocardial zonula adherens protein (MYZAP).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Myocardial zonula adherens protein (MYZAP).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Myocardial zonula adherens protein (MYZAP).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Myocardial zonula adherens protein (MYZAP).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Myocardial zonula adherens protein (MYZAP).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Myocardial zonula adherens protein (MYZAP).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Myocardial zonula adherens protein (MYZAP).	[14]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Myocardial zonula adherens protein (MYZAP).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Myocardial zonula adherens protein (MYZAP).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Myocardial zonula adherens protein (MYZAP).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myocardial zonula adherens protein (MYZAP).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Myocardial zonula adherens protein (MYZAP).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Myocardial zonula adherens protein (MYZAP).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Myocardial zonula adherens protein (MYZAP).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myocardial zonula adherens protein (MYZAP).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Myocardial zonula adherens protein (MYZAP).	[21]

References

• [1] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [2] Patients affected by a new variant of endemic pemphigus foliaceus have autoantibodies colocalizing with MYZAP, p0071, desmoplakins 1-2 and ARVCF, causing renal damage.Clin Exp Dermatol. 2018 Aug;43(6):692-702. doi: 10.1111/ced.13566. Epub 2018 May 16.
• [3] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [4] Remodelling of myocardial intercalated disc protein connexin 43 causes increased susceptibility to malignant arrhythmias in ARVC/D patients.Forensic Sci Int. 2017 Jun;275:14-22. doi: 10.1016/j.forsciint.2017.02.020. Epub 2017 Feb 27.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [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] 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.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] 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.
• [16] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [17] 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.
• [18] 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.
• [19] Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.