Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLRH78U)

• DOT Name: N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1)
• Synonyms: EC 2.1.1.244; Alpha N-terminal protein methyltransferase 1A; Methyltransferase-like protein 11A; N-terminal RCC1 methyltransferase; X-Pro-Lys N-terminal protein methyltransferase 1A; NTM1A
• Gene Name: NTMT1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: NTM1A_HUMAN
• PDB ID: 2EX4; 5CVD; 5CVE; 5E1B; 5E1D; 5E1M; 5E1O; 5E2A; 5E2B; 6DTN; 6KDQ; 6PVA; 6PVB; 6WH8; 6WJ7; 7K3D; 7SS1; 7U1M
• EC Number: 2.1.1.244
• Pfam ID: PF05891
• Sequence:
  MTSEVIEDEKQFYSKAKTYWKQIPPTVDGMLGGYGHISSIDINSSRKFLQRFLREGPNKT
  GTSCALDCGAGIGRITKRLLLPLFREVDMVDITEDFLVQAKTYLGEEGKRVRNYFCCGLQ
  DFTPEPDSYDVIWIQWVIGHLTDQHLAEFLRRCKGSLRPNGIIVIKDNMAQEGVILDDVD
  SSVCRDLDVVRRIICSAGLSLLAEERQENLPDEIYHVYSFALR
• Function: Distributive alpha-N-methyltransferase that methylates the N-terminus of target proteins containing the N-terminal motif [Ala/Gly/Pro/Ser]-Pro-Lys when the initiator Met is cleaved. Specifically catalyzes mono-, di- or tri-methylation of the exposed alpha-amino group of the Ala, Gly or Ser residue in the [Ala/Gly/Ser]-Pro-Lys motif and mono- or di-methylation of Pro in the Pro-Pro-Lys motif. Some of the substrates may be primed by NTMT2-mediated monomethylation. Catalyzes the trimethylation of the N-terminal Gly in CENPA (after removal of Met-1). Responsible for the N-terminal methylation of KLHL31, MYL2, MYL3, RB1, RCC1, RPL23A and SET. Required during mitosis for normal bipolar spindle formation and chromosome segregation via its action on RCC1.
• BioCyc Pathway: MetaCyc:ENSG00000148335-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[1]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[1]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

6 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 N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-terminal Xaa-Pro-Lys N-methyltransferase 1 (NTMT1).	[7]

References

• [1] Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N-terminal trimethylation.Protein Sci. 2017 Aug;26(8):1639-1652. doi: 10.1002/pro.3202. Epub 2017 Jun 11.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [7] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.