Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO9IDFD)

• DOT Name: Transmembrane protein 64 (TMEM64)
• Gene Name: TMEM64
• Related Disease:
  Osteoporosis
  Prostate neoplasm
• UniProt ID: TMM64_HUMAN
• Pfam ID: PF09335
• Sequence:
  MRSPGGILLQALPRLLQHAALPGLAELPARWALPRGAGGDGPADRLPRGGGASAAAAAAA
  ASGALLGAYLERHGPPEASELPEPGGALAGGPGSGGGGVVVGVAEVRNWRCCCLGSTCWC
  RSLVLVCVLAALCFASLALVRRYLHHLLLWVESLDSLLGVLLFVVGFIVVSFPCGWGYIV
  LNVAAGYLYGFVLGMGLMMVGVLIGTFIAHVVCKRLLTAWVAARIQSSEKLSAVIRVVEG
  GSGLKVVALARLTPIPFGLQNAVFSITDLSLPNYLMASSVGLLPTQLLNSYLGTTLRTME
  DVIAEQSVSGYFVFCLQIIISIGLMFYVVHRAQVELNAAIVACEMELKSSLVKGNQPNTS
  GSSFYNKRTLTFSGGGINVV
• Function: Positively regulates TNFSF11-induced osteoclast differentiation. Acts as a regulator of TNFSF11-mediated Ca(2+) signaling pathways via its interaction with SERCA2 which is critical for the TNFSF11-induced CREB1 activation and mitochondrial ROS generation necessary for proper osteoclast generation. Association between TMEM64 and SERCA2 in the ER leads to cytosolic Ca (2+) spiking for activation of NFATC1 and production of mitochondrial ROS, thereby triggering Ca (2+) signaling cascades that promote osteoclast differentiation and activation. Negatively regulates osteoblast differentiation and positively regulates adipocyte differentiation via modulation of the canonical Wnt signaling pathway. Mediates the switch in lineage commitment to osteogenesis rather than to adipogenesis in mesenchymal stem cells by negatively regulating the expression, activity and nuclear localization of CTNNB1.
• KEGG Pathway: Osteoclast differentiation (hsa04380)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteoporosis	DISF2JE0	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]

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 64 (TMEM64).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protein 64 (TMEM64).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transmembrane protein 64 (TMEM64).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane protein 64 (TMEM64).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transmembrane protein 64 (TMEM64).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane protein 64 (TMEM64).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transmembrane protein 64 (TMEM64).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transmembrane protein 64 (TMEM64).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Transmembrane protein 64 (TMEM64).	[10]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Transmembrane protein 64 (TMEM64).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transmembrane protein 64 (TMEM64).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Transmembrane protein 64 (TMEM64).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Transmembrane protein 64 (TMEM64).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane protein 64 (TMEM64).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Transmembrane protein 64 (TMEM64).	[13]

References

• [1] Altered Levels of mRNAs for Calcium-Binding/Associated Proteins, Annexin A1, S100A4, and TMEM64, in Peripheral Blood Mononuclear Cells Are Associated with Osteoporosis.Dis Markers. 2019 Nov 11;2019:3189520. doi: 10.1155/2019/3189520. eCollection 2019.
• [2] Transmembrane protein 64 modulates prostate tumor progression by regulating Wnt3a secretion.Oncol Lett. 2019 Jul;18(1):283-290. doi: 10.3892/ol.2019.10324. Epub 2019 May 6.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology. 2008 Oct;149(10):4809-20. doi: 10.1210/en.2008-0035. Epub 2008 Jun 12.
• [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] 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.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.