Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVJ0GA)

• DOT Name: Putative divalent cation/proton antiporter TMEM165 (TMEM165)
• Synonyms: Transmembrane protein 165; Transmembrane protein PT27; Transmembrane protein TPARL
• Gene Name: TMEM165
• Related Disease:
  Amelogenesis imperfecta
  TMEM165-congenital disorder of glycosylation
  Bone development disease
  Advanced cancer
  Hepatocellular carcinoma
• UniProt ID: TM165_HUMAN
• Pfam ID: PF01169
• Sequence:
  MAAAAPGNGRASAPRLLLLFLVPLLWAPAAVRAGPDEDLSHRNKEPPAPAQQLQPQPVAV
  QGPEPARVEKIFTPAAPVHTNKEDPATQTNLGFIHAFVAAISVIIVSELGDKTFFIAAIM
  AMRYNRLTVLAGAMLALGLMTCLSVLFGYATTVIPRVYTYYVSTVLFAIFGIRMLREGLK
  MSPDEGQEELEEVQAELKKKDEEFQRTKLLNGPGDVETGTSITVPQKKWLHFISPIFVQA
  LTLTFLAEWGDRSQLTTIVLAAREDPYGVAVGGTVGHCLCTGLAVIGGRMIAQKISVRTV
  TIIGGIVFLAFAFSALFISPDSGF
• Function: Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane. Mediates the reversible transport of calcium or manganese to the Golgi lumen driven by the proton gradient and possibly the membrane potential generated by V-ATPase. Provides calcium or manganese cofactors to resident Golgi enzymes and contributes to the maintenance of an acidic luminal Golgi pH required for proper functioning of the secretory pathway. Promotes Ca(2+) storage within the Golgi lumen of the mammary epithelial cells to be then secreted into milk. The transport mechanism and stoichiometry remains to be elucidated.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta	DISGYR9E	Definitive	Biomarker	[1]
TMEM165-congenital disorder of glycosylation	DISPHFU3	Definitive	Autosomal recessive	[1]
Bone development disease	DISVKAZS	moderate	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[3]

7 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 Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[9]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Putative divalent cation/proton antiporter TMEM165 (TMEM165).	[10]

References

• [1] TMEM165 deficiency causes a congenital disorder of glycosylation. Am J Hum Genet. 2012 Jul 13;91(1):15-26. doi: 10.1016/j.ajhg.2012.05.002. Epub 2012 Jun 7.
• [2] Abnormal cartilage development and altered N-glycosylation in Tmem165-deficient zebrafish mirrors the phenotypes associated with TMEM165-CDG.Glycobiology. 2015 Jun;25(6):669-82. doi: 10.1093/glycob/cwv009. Epub 2015 Jan 21.
• [3] TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma and its depletion impairs invasion activity.Oncol Rep. 2018 Sep;40(3):1297-1306. doi: 10.3892/or.2018.6565. Epub 2018 Jul 12.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] 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.
• [9] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [10] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.