Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT50CTOJ)

• DOT Name: Transcription termination factor 4, mitochondrial (MTERF4)
• Synonyms: Mitochondrial transcription termination factor 4; mTERF domain-containing protein 2
• Gene Name: MTERF4
• Related Disease:
  Alzheimer disease
  Bipolar disorder
  Major depressive disorder
  Schizophrenia
• UniProt ID: MTEF4_HUMAN
• PDB ID: 4FP9; 4FZV; 7O9K; 7O9M; 7ODR; 7ODS; 7ODT; 7OF0; 7OF3; 7OF5; 7OF7; 7OIC; 7PD3
• Pfam ID: PF02536
• Sequence:
  MAAFGRQVLDWHRLIPLTWACMARQTPHLGEQRRTTASLLRKLTTASNGGVIEELSCVRS
  NNYVQEPECRRNLVQCLLEKQGTPVVQGSLELERVMSSLLDMGFSNAHINELLSVRRGAS
  LQQLLDIISEFILLGLNPEPVCVVLKKSPQLLKLPIMQMRKRSSYLQKLGLGEGKLKRVL
  YCCPEIFTMRQQDINDTVRLLKEKCLFTVQQVTKILHSCPSVLREDLGQLEYKFQYAYFR
  MGIKHPDIVKSEYLQYSLTKIKQRHIYLERLGRYQTPDKKGQTQIPNPLLKDILRVSEAE
  FLARTACTSVEEFQVFKKLLAREEEESESSTSDDKRASLDEDEDDDDEEDNDEDDNDEDD
  DDEDDDEAEDNDEDEDDDEEE
• Function: Regulator of mitochondrial ribosome biogenesis and translation. Binds to mitochondrial ribosomal RNAs 16S, 12S and 7S and targets NSUN4 RNA methyltransferase to the mitochondrial large ribosomal subunit (39S).
• Reactome Pathway: rRNA modification in the mitochondrion (R-HSA-6793080)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]

10 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 Transcription termination factor 4, mitochondrial (MTERF4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[10]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[12]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Transcription termination factor 4, mitochondrial (MTERF4).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcription termination factor 4, mitochondrial (MTERF4).	[11]

References

• [1] Overexpression of MTERF4 promotes the amyloidogenic processing of APP by inhibiting ADAM10.Biochem Biophys Res Commun. 2017 Jan 22;482(4):928-934. doi: 10.1016/j.bbrc.2016.11.135. Epub 2016 Nov 25.
• [2] Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs.J Psychopharmacol. 2015 Aug;29(8):884-91. doi: 10.1177/0269881115584469. Epub 2015 May 5.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.