Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRG1DOY)

• DOT Name: Transmembrane protein 33 (TMEM33)
• Synonyms: Protein DB83; SHINC-3
• Gene Name: TMEM33
• UniProt ID: TMM33_HUMAN
• Pfam ID: PF03661
• Sequence:
  MADTTPNGPQGAGAVQFMMTNKLDTAMWLSRLFTVYCSALFVLPLLGLHEAASFYQRALL
  ANALTSALRLHQRLPHFQLSRAFLAQALLEDSCHYLLYSLIFVNSYPVTMSIFPVLLFSL
  LHAATYTKKVLDARGSNSLPLLRSVLDKLSANQQNILKFIACNEIFLMPATVFMLFSGQG
  SLLQPFIYYRFLTLRYSSRRNPYCRTLFNELRIVVEHIIMKPACPLFVRRLCLQSIAFIS
  RLAPTVP
• Function: Acts as a regulator of the tubular endoplasmic reticulum (ER) network by modulating intracellular calcium homeostasis. Mechanistically, stimulates PKD2 calcium-dependent activity. Suppresses the RTN3/4-induced formation of the ER tubules. Positively regulates PERK-mediated and IRE1-mediated unfolded protein response signaling. Plays an essential role in VEGF-mediated release of Ca(2+) from ER stores during angiogenesis. Also plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26. Participates in lipid metabolism by acting as a downstream effector of the pyruvate kinase/PKM. Forms a complex with RNF5 to facilitate polyubiquitination and subsequent degradation of SCAP on the ER membrane.
• Tissue Specificity: Prostate cancer and several cancer cell lines (at protein level). Widely expressed. Expressed at higher levels in endocrine-resistant breast cancer cells as compared to endocrine-sensitive breast cancer cells. Expressed at higher levels in early recurrence breast cancer tissues as compared to non-recurrent breast tumors.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)

Molecular Interaction Atlas (MIA) of This DOT

11 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 protein 33 (TMEM33).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane protein 33 (TMEM33).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Transmembrane protein 33 (TMEM33).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transmembrane protein 33 (TMEM33).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane protein 33 (TMEM33).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transmembrane protein 33 (TMEM33).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Transmembrane protein 33 (TMEM33).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Transmembrane protein 33 (TMEM33).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transmembrane protein 33 (TMEM33).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Transmembrane protein 33 (TMEM33).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transmembrane protein 33 (TMEM33).	[12]

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 protein 33 (TMEM33).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [6] 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.
• [7] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [8] 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.
• [9] 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.
• [10] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [11] 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.
• [12] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.