Details of Drug Off-Target (DOT)

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

• DOT Name: ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT)
• Synonyms: EC 2.1.1.-; Protein N-lysine methyltransferase FAM173B; hFAM173B
• Gene Name: ATPSCKMT
• Related Disease: Neuralgia
• UniProt ID: ACKMT_HUMAN
• EC Number: 2.1.1.-
• Sequence:
  MEGGGGIPLETLKEESQSRHVLPASFEVNSLQKSNWGFLLTGLVGGTLVAVYAVATPFVT
  PALRKVCLPFVPATTKQIENVVKMLRCRRGSLVDIGSGDGRIVIAAAKKGFTAVGYELNP
  WLVWYSRYRAWREGVHGSAKFYISDLWKVTFSQYSNVVIFGVPQMMLQLEKKLERELEDD
  ARVIACRFPFPHWTPDHVTGEGIDTVWAYDASTFRGREKRPCTSMHFQLPIQA
• Function: Mitochondrial protein-lysine N-methyltransferase that trimethylates ATP synthase subunit C, ATP5MC1 and ATP5MC2. Trimethylation is required for proper incorporation of the C subunit into the ATP synthase complex and mitochondrial respiration. Promotes chronic pain. Involved in persistent inflammatory and neuropathic pain: methyltransferase activity in the mitochondria of sensory neurons promotes chronic pain via a pathway that depends on the production of reactive oxygen species (ROS) and on the engagement of spinal cord microglia.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuralgia	DISWO58J	Strong	Biomarker	[1]

8 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 ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP synthase subunit C lysine N-methyltransferase (ATPSCKMT).	[9]

References

• [1] Identification of FAM173B as a protein methyltransferase promoting chronic pain.PLoS Biol. 2018 Feb 14;16(2):e2003452. doi: 10.1371/journal.pbio.2003452. eCollection 2018 Feb.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.