Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6QGM5Y)

• DOT Name: Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1)
• Synonyms: IMP dehydrogenase 1; IMPD 1; IMPDH 1; EC 1.1.1.205; IMPDH-I
• Gene Name: IMPDH1
• Related Disease:
  Inherited retinal dystrophy
  Leber congenital amaurosis 11
  Retinitis pigmentosa 10
  Leber congenital amaurosis
  Retinitis pigmentosa
• UniProt ID: IMDH1_HUMAN
• PDB ID: 1JCN; 7RER; 7RES; 7RFE; 7RFF; 7RFG; 7RFH; 7RFI; 7RGD; 7RGI; 7RGL; 7RGM; 7RGQ
• EC Number: 1.1.1.205
• Pfam ID: PF00571 ; PF00478
• Sequence:
  MADYLISGGTGYVPEDGLTAQQLFASADGLTYNDFLILPGFIDFIADEVDLTSALTRKIT
  LKTPLISSPMDTVTEADMAIAMALMGGIGFIHHNCTPEFQANEVRKVKKFEQGFITDPVV
  LSPSHTVGDVLEAKMRHGFSGIPITETGTMGSKLVGIVTSRDIDFLAEKDHTTLLSEVMT
  PRIELVVAPAGVTLKEANEILQRSKKGKLPIVNDCDELVAIIARTDLKKNRDYPLASKDS
  QKQLLCGAAVGTREDDKYRLDLLTQAGVDVIVLDSSQGNSVYQIAMVHYIKQKYPHLQVI
  GGNVVTAAQAKNLIDAGVDGLRVGMGCGSICITQEVMACGRPQGTAVYKVAEYARRFGVP
  IIADGGIQTVGHVVKALALGASTVMMGSLLAATTEAPGEYFFSDGVRLKKYRGMGSLDAM
  EKSSSSQKRYFSEGDKVKIAQGVSGSIQDKGSIQKFVPYLIAGIQHGCQDIGARSLSVLR
  SMMYSGELKFEKRTMSAQIEGGVHGLHSYEKRLY
• Function: Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism. It may also have a role in the development of malignancy and the growth progression of some tumors.
• Tissue Specificity: IMP type I is the main species in normal leukocytes and type II predominates over type I in the tumor.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)
  Potential therapeutics for SARS (R-HSA-9679191)
  Azathioprine ADME (R-HSA-9748787)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS02896-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal dominant	[1]
Leber congenital amaurosis 11	DISK5MO8	Definitive	Autosomal dominant	[2]
Retinitis pigmentosa 10	DIS30DJI	Definitive	Autosomal dominant	[3]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[4]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Azathioprine	DMMZSXQ	Approved	Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1) affects the response to substance of Azathioprine.	[23]

2 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 Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[21]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Inosine-5'-monophosphate dehydrogenase 1 (IMPDH1).	[22]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Phenotypic variability associated with the D226N allele of IMPDH1. Ophthalmology. 2015 Feb;122(2):429-31. doi: 10.1016/j.ophtha.2014.07.057. Epub 2014 Nov 13.
• [4] Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006 Jan;47(1):34-42. doi: 10.1167/iovs.05-0868.
• [5] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Multifaceted preventive effects of single agent quercetin on a human prostate adenocarcinoma cell line (PC-3): implications for nutritional transcriptomics and multi-target therapy. Med Oncol. 2011 Dec;28(4):1395-404. doi: 10.1007/s12032-010-9603-3. Epub 2010 Jul 2.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 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.
• [17] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [23] IMPDH1 promoter mutations in a patient exhibiting azathioprine resistance. Pharmacogenomics J. 2007 Oct;7(5):312-7. doi: 10.1038/sj.tpj.6500421. Epub 2006 Oct 17.