Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQIR8LF)

• DOT Name: Adenosine 5'-monophosphoramidase HINT1 (HINT1)
• Synonyms: EC 3.9.1.-; Desumoylating isopeptidase HINT1; EC 3.4.22.-; Histidine triad nucleotide-binding protein 1; Protein kinase C inhibitor 1; Protein kinase C-interacting protein 1; PKCI-1
• Gene Name: HINT1
• Related Disease:
  Charcot marie tooth disease
  Gamstorp-Wohlfart syndrome
• UniProt ID: HINT1_HUMAN
• PDB ID: 1AV5 ; 1KPA ; 1KPB ; 1KPC ; 1KPE ; 1KPF ; 3TW2 ; 4EQE ; 4EQG ; 4EQH ; 4ZKL ; 4ZKV ; 5ED3 ; 5ED6 ; 5EMT ; 5I2E ; 5I2F ; 5IPB ; 5IPC ; 5IPD ; 5IPE ; 5KLY ; 5KLZ ; 5KM0 ; 5KM1 ; 5KM2 ; 5KM3 ; 5KM4 ; 5KM6 ; 5KMA ; 5KMB ; 5KMC ; 5O8I ; 5WA8 ; 5WA9 ; 5WAA ; 6B42 ; 6G9Z ; 6J53 ; 6J58 ; 6J5S ; 6J5Z ; 6J64 ; 6J65 ; 6N3V ; 6N3W ; 6N3X ; 6N3Y ; 6YQM ; 7Q2U ; 8P8P ; 8PA6 ; 8PA9 ; 8PAF ; 8PAI ; 8WZD
• EC Number: 3.4.22.-; 3.9.1.-
• Pfam ID: PF01230
• Sequence:
  MADEIAKAQVARPGGDTIFGKIIRKEIPAKIIFEDDRCLAFHDISPQAPTHFLVIPKKHI
  SQISVAEDDDESLLGHLMIVGKKCAADLGLNKGYRMVVNEGSDGGQSVYHVHLHVLGGRQ
  MHWPPG
• Function: Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2. Hydrolyzes adenosine 5'monophosphomorpholidate (AMP-morpholidate) and guanosine 5'monophosphomorpholidate (GMP-morpholidate). Hydrolyzes lysyl-AMP (AMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) generated by lysine tRNA ligase, as well as Met-AMP, His-AMP and Asp-AMP, lysyl-GMP (GMP-N-epsilon-(N-alpha-acetyl lysine methyl ester)) and AMP-N-alanine methyl ester. Hydrolyzes 3-indolepropionic acyl-adenylate, tryptamine adenosine phosphoramidate monoester and other fluorogenic purine nucleoside tryptamine phosphoramidates in vitro. Can also convert adenosine 5'-O-phosphorothioate and guanosine 5'-O-phosphorothioate to the corresponding nucleoside 5'-O-phosphates with concomitant release of hydrogen sulfide. In addition, functions as scaffolding protein that modulates transcriptional activation by the LEF1/TCF1-CTNNB1 complex and by the complex formed with MITF and CTNNB1. Modulates p53/TP53 levels and p53/TP53-mediated apoptosis. Modulates proteasomal degradation of target proteins by the SCF (SKP2-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Also exhibits SUMO-specific isopeptidase activity, deconjugating SUMO1 from RGS17. Deconjugates SUMO1 from RANGAP1.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot marie tooth disease	DIS3BT2L	Definitive	Autosomal recessive	[1]
Gamstorp-Wohlfart syndrome	DISZ4XRU	Definitive	Autosomal recessive	[2]

14 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 Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[11]
EXISULIND	DMBY56U	Phase 3	EXISULIND increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[15]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Adenosine 5'-monophosphoramidase HINT1 (HINT1).	[7]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012 Oct;44(10):1080-3. doi: 10.1038/ng.2406. Epub 2012 Sep 9.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [8] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [11] Association of the histidine-triad nucleotide-binding protein-1 (HINT1) gene variants with nicotine dependence. Pharmacogenomics J. 2011 Aug;11(4):251-7. doi: 10.1038/tpj.2010.41. Epub 2010 Jun 1.
• [12] Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1. Cancer Res. 2008 Jul 1;68(13):5355-62.
• [13] Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.