Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH76ZWK)

• DOT Name: Sigma intracellular receptor 2 (TMEM97)
• Synonyms: S2R; Sigma-2 receptor; Sigma2 receptor; Meningioma-associated protein 30; MAC30; Transmembrane protein 97
• Gene Name: TMEM97
• UniProt ID: SGMR2_HUMAN
• Pfam ID: PF05241
• Sequence:
  MGAPATRRCVEWLLGLYFLSHIPITLFMDLQAVLPRELYPVEFRNLLKWYAKEFKDPLLQ
  EPPAWFKSFLFCELVFQLPFFPIATYAFLKGSCKWIRTPAIIYSVHTMTTLIPILSTFLF
  EDFSKASGFKGQRPETLHERLTLVSVYAPYLLIPFILLIFMLRSPYYKYEEKRKKK
• Function: Sigma-2 receptor which contributes to ameliorate dysfunctional cellular processes and slow degenerative progression by regulating cell functions including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface (Probable). Forms a ternary complex with PGRMC1 receptor and low density lipoprotein receptor/LDLR at the plasma membrane, which increases LDLR-mediated LDL cholesterol internalization. Decreases lysosomal sterol transporter NPC1 availability to the cell, probably through NPC1-binding, hence controlling lipid transport, including cholesterol and LBPA, outside of late endosome/lysosome. Binds regio- and stereoselective ligand 20(S)-hydroxycholesterol (20(S)-OHC) which enhances TMEM97-NPC1 interaction and decreases TMEM97-PGRMC1 and TMEM97-TSPO interactions, thereby linking OHC binding to cholesterol homeostasis. Also able to bind cholesterol. Binds histatin 1 (Hst 1)/HN1 salivary peptide at the ER membrane, which is critical for increasing mitochondria-ER contacts and stimulating Hst1 wound healing properties. May alter the activity of some cytochrome P450 proteins. Although shows homologies with sterol isomerases (EXPERA domain), not able to catalyze sterol isomerization (Probable). However, may act as sensors of these molecules (Probable). Acts as a quality control factor in the ER, promoting the proteolytic degradation of nonproductive and extramitochondrial precursor proteins in the ER membrane thus removing them from the ER surface.
• Tissue Specificity: Widely expressed in normal tissues. Expressed in pancreatic, renal, breast, colon, ovarian surface epithelial (OSE) cells. Highly expressed in various proliferating cancer cells .
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Sigma intracellular receptor 2 (TMEM97) affects the response to substance of Etoposide.	[27]
Mitomycin	DMH0ZJE	Approved	Sigma intracellular receptor 2 (TMEM97) affects the response to substance of Mitomycin.	[27]
Topotecan	DMP6G8T	Approved	Sigma intracellular receptor 2 (TMEM97) affects the response to substance of Topotecan.	[27]
Vinblastine	DM5TVS3	Approved	Sigma intracellular receptor 2 (TMEM97) affects the response to substance of Vinblastine.	[27]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	Sigma intracellular receptor 2 (TMEM97) affects the metabolism of ANW-32821.	[10]

28 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 Sigma intracellular receptor 2 (TMEM97).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sigma intracellular receptor 2 (TMEM97).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sigma intracellular receptor 2 (TMEM97).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Sigma intracellular receptor 2 (TMEM97).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sigma intracellular receptor 2 (TMEM97).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Sigma intracellular receptor 2 (TMEM97).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sigma intracellular receptor 2 (TMEM97).	[6]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[16]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Sigma intracellular receptor 2 (TMEM97).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sigma intracellular receptor 2 (TMEM97).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[4]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sigma intracellular receptor 2 (TMEM97).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Sigma intracellular receptor 2 (TMEM97).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Sigma intracellular receptor 2 (TMEM97).	[26]

References

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• [21] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
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• [23] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
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• [27] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.