Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6N5J2)

• DOT Name: Cell cycle control protein 50A (TMEM30A)
• Synonyms: P4-ATPase flippase complex beta subunit TMEM30A; Transmembrane protein 30A
• Gene Name: TMEM30A
• Related Disease:
  Cerebellar ataxia
  Neoplasm
  Progressive familial intrahepatic cholestasis type 1
  Prostate cancer
  Prostate carcinoma
  leukaemia
  Leukemia
  Intrahepatic cholestasis
• UniProt ID: CC50A_HUMAN
• PDB ID: 6K7G; 6K7H; 6K7I; 6K7J; 6K7K; 6K7L; 6K7M; 6K7N; 6LKN; 7BSP; 7BSQ; 7BSS; 7BSU; 7BSV; 7BSW; 7PY4; 7VGI; 7VGJ; 7VSG; 7VSH; 8OX4; 8OX5; 8OX6; 8OX7; 8OX8; 8OX9; 8OXA; 8OXB; 8OXC
• Pfam ID: PF03381
• Sequence:
  MAMNYNAKDEVDGGPPCAPGGTAKTRRPDNTAFKQQRLPAWQPILTAGTVLPIFFIIGLI
  FIPIGIGIFVTSNNIREIEIDYTGTEPSSPCNKCLSPDVTPCFCTINFTLEKSFEGNVFM
  YYGLSNFYQNHRRYVKSRDDSQLNGDSSALLNPSKECEPYRRNEDKPIAPCGAIANSMFN
  DTLELFLIGNDSYPIPIALKKKGIAWWTDKNVKFRNPPGGDNLEERFKGTTKPVNWLKPV
  YMLDSDPDNNGFINEDFIVWMRTAALPTFRKLYRLIERKSDLHPTLPAGRYSLNVTYNYP
  VHYFDGRKRMILSTISWMGGKNPFLGIAYIAVGSISFLLGVVLLVINHKYRNSSNTADIT
  I
• Function: Accessory component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric distribution of phospholipids. Phospholipid translocation seems also to be implicated in vesicle formation and in uptake of lipid signaling molecules. The beta subunit may assist in binding of the phospholipid substrate. Required for the proper folding, assembly and ER to Golgi exit of the ATP8A2:TMEM30A flippase complex. ATP8A2:TMEM30A may be involved in regulation of neurite outgrowth, and, reconstituted to liposomes, predomiminantly transports phosphatidylserine (PS) and to a lesser extent phosphatidylethanolamine (PE). The ATP8A1:TMEM30A flippase complex seems to play a role in regulation of cell migration probably involving flippase-mediated translocation of phosphatidylethanolamine (PE) at the plasma membrane. Required for the formation of the ATP8A2, ATP8B1 and ATP8B2 P-type ATPAse intermediate phosphoenzymes. Involved in uptake of platelet-activating factor (PAF), synthetic drug alkylphospholipid edelfosine, and, probably in association with ATP8B1, of perifosine. Also mediates the export of alpha subunits ATP8A1, ATP8B1, ATP8B2, ATP8B4, ATP10A, ATP10B, ATP10D, ATP11A, ATP11B and ATP11C from the ER to other membrane localizations.
• KEGG Pathway: Efferocytosis (hsa04148)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Progressive familial intrahepatic cholestasis type 1	DISU0AJE	Strong	Genetic Variation	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
leukaemia	DISS7D1V	moderate	Biomarker	[5]
Leukemia	DISNAKFL	moderate	Biomarker	[5]
Intrahepatic cholestasis	DISHITDZ	Limited	Biomarker	[6]

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 Cell cycle control protein 50A (TMEM30A).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cell cycle control protein 50A (TMEM30A).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cell cycle control protein 50A (TMEM30A).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cell cycle control protein 50A (TMEM30A).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cell cycle control protein 50A (TMEM30A).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cell cycle control protein 50A (TMEM30A).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cell cycle control protein 50A (TMEM30A).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Cell cycle control protein 50A (TMEM30A).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Cell cycle control protein 50A (TMEM30A).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cell cycle control protein 50A (TMEM30A).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cell cycle control protein 50A (TMEM30A).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Cell cycle control protein 50A (TMEM30A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cell cycle control protein 50A (TMEM30A).	[16]

References

• [1] Disruption of Tmem30a results in cerebellar ataxia and degeneration of Purkinje cells.Cell Death Dis. 2018 Sep 5;9(9):899. doi: 10.1038/s41419-018-0938-6.
• [2] A biosystems approach to identify the molecular signaling mechanisms of TMEM30A during tumor migration.PLoS One. 2017 Jun 22;12(6):e0179900. doi: 10.1371/journal.pone.0179900. eCollection 2017.
• [3] Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1.Hepatology. 2009 Nov;50(5):1597-605. doi: 10.1002/hep.23158.
• [4] Novel biomarkers for prostate cancer including noncoding transcripts.Am J Pathol. 2009 Dec;175(6):2264-76. doi: 10.2353/ajpath.2009.080868. Epub 2009 Nov 5.
• [5] Tmem30a Plays Critical Roles in Ensuring the Survival of Hematopoietic Cells and Leukemia Cells in Mice.Am J Pathol. 2018 Jun;188(6):1457-1468. doi: 10.1016/j.ajpath.2018.02.015. Epub 2018 Mar 21.
• [6] Hepatic Tmem30a Deficiency Causes Intrahepatic Cholestasis by Impairing Expression and Localization of Bile Salt Transporters.Am J Pathol. 2017 Dec;187(12):2775-2787. doi: 10.1016/j.ajpath.2017.08.011. Epub 2017 Sep 15.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.