Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDBR8D1)

• DOT Name: Essential MCU regulator, mitochondrial (SMDT1)
• Synonyms: Single-pass membrane protein with aspartate-rich tail 1, mitochondrial
• Gene Name: SMDT1
• Related Disease:
  Advanced cancer
  Matthew-Wood syndrome
  Neoplasm
  Neuromuscular disease
• UniProt ID: EMRE_HUMAN
• PDB ID: 6K7X; 6K7Y; 6O58; 6O5B; 6WDN; 6WDO; 6XJV; 6XJX
• Pfam ID: PF10161
• Sequence:
  MASGAARWLVLAPVRSGALRSGPSLRKDGDVSAAWSGSGRSLVPSRSVIVTRSGAILPKP
  VKMSFGLLRVFSIVIPFLYVGTLISKNFAALLEEHDIFVPEDDDDDD
• Function: Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria. Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU. Plays a central role in regulating the uniplex complex response to intracellular calcium signaling. Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling.
• Reactome Pathway:
  Processing of SMDT1 (R-HSA-8949664)
  Mitochondrial calcium ion transport (R-HSA-8949215)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[2]

5 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 Essential MCU regulator, mitochondrial (SMDT1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Essential MCU regulator, mitochondrial (SMDT1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Essential MCU regulator, mitochondrial (SMDT1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Essential MCU regulator, mitochondrial (SMDT1).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Essential MCU regulator, mitochondrial (SMDT1).	[8]

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 Essential MCU regulator, mitochondrial (SMDT1).	[6]

References

• [1] SMDT1-driven change in mitochondrial dynamics mediate cell apoptosis in PDAC.Biochem Biophys Res Commun. 2019 Apr 2;511(2):323-329. doi: 10.1016/j.bbrc.2019.02.043. Epub 2019 Feb 16.
• [2] Proteolytic control of the mitochondrial calcium uniporter complex.Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4388-4393. doi: 10.1073/pnas.1702938114. Epub 2017 Apr 10.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.