Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7VB4AM)

• DOT Name: Mitochondrial dynamics protein MID49 (MIEF2)
• Synonyms: Mitochondrial dynamics protein of 49 kDa; Mitochondrial elongation factor 2; Smith-Magenis syndrome chromosomal region candidate gene 7 protein
• Gene Name: MIEF2
• Related Disease:
  Combined oxidative phosphorylation deficiency 49
  Mitochondrial myopathy
• UniProt ID: MID49_HUMAN
• PDB ID: 5WP9
• Pfam ID: PF20266 ; PF21297
• Sequence:
  MAEFSQKRGKRRSDEGLGSMVDFLLANARLVLGVGGAAVLGIATLAVKRFIDRATSPRDE
  DDTKADSWKELSLLKATPHLQPRPPPAALSQPVLPLAPSSSAPEGPAETDPEVTPQLSSP
  APLCLTLQERLLAFERDRVTIPAAQVALAKQLAGDIALELQAYFRSKFPELPFGAFVPGG
  PLYDGLQAGAADHVRLLVPLVLEPGLWSLVPGVDTVARDPRCWAVRRTQLEFCPRGSSPW
  DRFLVGGYLSSRVLLELLRKALAASVNWPAIGSLLGCLIRPSMASEELLLEVQHERLELT
  VAVLVAVPGVDADDRLLLAWPLEGLAGNLWLQDLYPVEAARLRALDDHDAGTRRRLLLLL
  CAVCRGCSALGQLGRGHLTQVVLRLGEDNVDWTEEALGERFLQALELLIGSLEQASLPCH
  FNPSVNLFSSLREEEIDDIGYALYSGLQEPEGLL
• Function: Mitochondrial outer membrane protein involved in the regulation of mitochondrial organization. It is required for mitochondrial fission and promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface independently of the mitochondrial fission FIS1 and MFF proteins. Regulates DNM1L GTPase activity.
• Tissue Specificity: Expressed in all tissues tested with highest expression in heart and skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation deficiency 49	DIS8YDIH	Limited	Unknown	[1]
Mitochondrial myopathy	DIS9SA7V	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Mitochondrial dynamics protein MID49 (MIEF2).	[3]

7 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 Mitochondrial dynamics protein MID49 (MIEF2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial dynamics protein MID49 (MIEF2).	[10]

References

• [1] Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014 Jul 2;312(1):68-77. doi: 10.1001/jama.2014.7184.
• [2] A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies.Hum Mol Genet. 2018 Apr 1;27(7):1186-1195. doi: 10.1093/hmg/ddy033.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.