Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZQJD3)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13)
• Gene Name: TIMM13
• Related Disease: Advanced cancer
• UniProt ID: TIM13_HUMAN
• Pfam ID: PF02953
• Sequence:
  MEGGFGSDFGGSGSGKLDPGLIMEQVKVQIAVANAQELLQRMTDKCFRKCIGKPGGSLDN
  SEQKCIAMCMDRYMDAWNTVSRAYNSRLQRERANM
• Function: Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. Also required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space. The TIMM8-TIMM13 complex mediates the import of proteins such as TIMM23, SLC25A12/ARALAR1 and SLC25A13/ARALAR2, while the predominant TIMM9-TIMM10 70 kDa complex mediates the import of much more proteins.
• 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 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13) affects the response to substance of Paclitaxel.	[11]

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 import inner membrane translocase subunit Tim13 (TIMM13).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[5]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial import inner membrane translocase subunit Tim13 (TIMM13).	[10]

References

• [1] Breast cancer screening with digital breast tomosynthesis - 4 year experience and comparison with national data.J Chin Med Assoc. 2018 Jan;81(1):70-80. doi: 10.1016/j.jcma.2017.05.013. Epub 2017 Nov 9.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] 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.