Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2JUZ7Q)

• DOT Name: Transmembrane protein 65 (TMEM65)
• Gene Name: TMEM65
• Related Disease:
  Mitochondrial encephalomyopathy
  Mitochondrial myopathy
• UniProt ID: TMM65_HUMAN
• Pfam ID: PF10507
• Sequence:
  MSRLLPLLRSRTARSLRPGPAAAAAPRPPSWCCCGRGLLALAPPGGLPGGPRRLGTHPKK
  EPMEALNTAQGARDFIYSLHSTERSCLLKELHRFESIAIAQEKLEAPPPTPGQLRYVFIH
  NAIPFIGFGFLDNAIMIVAGTHIEMSIGIILGISTMAAAALGNLVSDLAGLGLAGYVEAL
  ASRLGLSIPDLTPKQVDMWQTRLSTHLGKAVGVTIGCILGMFPLIFFGGGEEDEKLETKS
• Function: Essential for maintaining proper cardiac intercalated disk (ICD) structure and function as well as cardiac conduction velocity in the heart. Its association with SCN1B is required for stabilizing the perinexus in the ICD and for localization of GJA1 and SCN5A to the ICD. May regulate the function of the gap junction protein GJA1 and may contribute to the stability and proper localization of GJA1 to cardiac intercalated disk thereby regulating gap junction communication. May also play a role in the regulation of mitochondrial respiration and mitochondrial DNA copy number maintenance.
• Tissue Specificity: Predominantly expressed the ventricular tissue (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial encephalomyopathy	DISA6PTN	Limited	Genetic Variation	[1]
Mitochondrial myopathy	DIS9SA7V	Limited	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transmembrane protein 65 (TMEM65).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane protein 65 (TMEM65).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane protein 65 (TMEM65).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Transmembrane protein 65 (TMEM65).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane protein 65 (TMEM65).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Transmembrane protein 65 (TMEM65).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transmembrane protein 65 (TMEM65).	[8]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Transmembrane protein 65 (TMEM65).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane protein 65 (TMEM65).	[10]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Transmembrane protein 65 (TMEM65).	[11]

References

• [1] A mutation in the TMEM65 gene results in mitochondrial myopathy with severe neurological manifestations.Eur J Hum Genet. 2017 Jun;25(6):744-751. doi: 10.1038/ejhg.2017.20. Epub 2017 Mar 15.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [6] 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.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.