Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CJH67)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B)
• Synonyms: Fracture callus protein 1; FxC1; Mitochondrial import inner membrane translocase subunit Tim9 B; TIMM10B; Tim10b
• Gene Name: TIMM10B
• UniProt ID: T10B_HUMAN
• PDB ID: 7CGP
• Pfam ID: PF02953
• Sequence:
  MERQQQQQQQLRNLRDFLLVYNRMTELCFQRCVPSLHHRALDAEEEACLHSCAGKLIHSN
  HRLMAAYVQLMPALVQRRIADYEAASAVPGVAAEQPGVSPSGS
• Function: Component of the TIM22 complex, a complex that mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. The TIM22 complex forms a twin-pore translocase that uses the membrane potential as the external driving force. In the TIM22 complex, it may act as a docking point for the soluble 70 kDa complex that guides the target proteins in transit through the aqueous mitochondrial intermembrane space.
• Tissue Specificity: Ubiquitous, with highest expression in heart, kidney, liver and skeletal muscle.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

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 Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[10]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[11]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[12]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Mitochondrial import inner membrane translocase subunit Tim10 B (TIMM10B).	[9]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [9] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.