Details of Drug Off-Target (DOT)

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

• DOT Name: Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1)
• Synonyms: PIMT; EC 2.1.1.77; L-isoaspartyl protein carboxyl methyltransferase; Protein L-isoaspartyl/D-aspartyl methyltransferase; Protein-beta-aspartate methyltransferase
• Gene Name: PCMT1
• Related Disease:
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Epilepsy
  Neural tube defect
  Parkinson disease
  Schizophrenia
  Advanced cancer
  Bladder cancer
  Female hypogonadism
  Urinary bladder cancer
  Urinary bladder neoplasm
  Anencephaly
  Glioma
  Malignant glioma
  Neuroblastoma
  Subarachnoid hemorrhage
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: PIMT_HUMAN
• PDB ID: 1I1N; 1KR5
• EC Number: 2.1.1.77
• Pfam ID: PF01135
• Sequence:
  MAWKSGGASHSELIHNLRKNGIIKTDKVFEVMLATDRSHYAKCNPYMDSPQSIGFQATIS
  APHMHAYALELLFDQLHEGAKALDVGSGSGILTACFARMVGCTGKVIGIDHIKELVDDSV
  NNVRKDDPTLLSSGRVQLVVGDGRMGYAEEAPYDAIHVGAAAPVVPQALIDQLKPGGRLI
  LPVGPAGGNQMLEQYDKLQDGSIKMKPLMGVIYVPLTDKEKQWSRWK
• Function: Initiates the repair of damaged proteins by catalyzing methyl esterification of L-isoaspartyl and D-aspartyl residues produced by spontaneous isomerization and racemization of L-aspartyl and L-asparaginyl residues in aging peptides and proteins. Acts on EIF4EBP2, microtubule-associated protein 2, calreticulin, clathrin light chains a and b, Ubiquitin C-terminal hydrolase isozyme L1, phosphatidylethanolamine-binding protein 1, stathmin, beta-synuclein and alpha-synuclein.
• Reactome Pathway: Protein repair (R-HSA-5676934)
• BioCyc Pathway: MetaCyc:HS04385-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[3]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[6]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[7]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[6]
Anencephaly	DISIYW6T	Disputed	Genetic Variation	[3]
Glioma	DIS5RPEH	Limited	Biomarker	[8]
Malignant glioma	DISFXKOV	Limited	Biomarker	[8]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[9]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[10]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[11]

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 Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[20]

14 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 Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[4]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[18]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[18]
Dopamine	DMPGUCF	Approved	Dopamine decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[4]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[14]
Lithium	DMZ3OU6	Phase 2	Lithium increases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[22]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[23]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT1).	[24]

References

• [1] PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism.Int J Mol Sci. 2018 May 16;19(5):1485. doi: 10.3390/ijms19051485.
• [2] New findings on SNP variants of human protein L-isoaspartyl methyltransferase that affect catalytic activity, thermal stability, and aggregation.PLoS One. 2018 Jun 1;13(6):e0198266. doi: 10.1371/journal.pone.0198266. eCollection 2018.
• [3] Maternal PCMT1 gene polymorphisms and the risk of neural tube defects in a Chinese population of Lvliang high-risk area.Gene. 2012 Sep 1;505(2):340-4. doi: 10.1016/j.gene.2012.05.035. Epub 2012 May 27.
• [4] Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells. Neuroscience. 2014 May 16;267:263-76. doi: 10.1016/j.neuroscience.2014.03.001. Epub 2014 Mar 12.
• [5] Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia.J Psychiatr Res. 2009 Jul;43(11):978-86. doi: 10.1016/j.jpsychires.2008.11.006. Epub 2008 Dec 24.
• [6] PCMT1 is an unfavorable predictor and functions as an oncogene in bladder cancer.IUBMB Life. 2018 Apr;70(4):291-299. doi: 10.1002/iub.1717. Epub 2018 Mar 8.
• [7] Association between polymorphisms in the protein L-isoaspartate (D-aspartate) O-methyltransferase gene and premature ovarian failure.Fertil Steril. 2009 Apr;91(4 Suppl):1362-5. doi: 10.1016/j.fertnstert.2008.03.078. Epub 2008 Jun 25.
• [8] Expression and activity of l-isoaspartyl methyltransferase decrease in stage progression of human astrocytic tumors.Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):93-103. doi: 10.1016/j.molbrainres.2004.12.008.
• [9] The protein l-isoaspartyl (d-aspartyl) methyltransferase protects against dopamine-induced apoptosis in neuroblastoma SH-SY5Y cells.Neuroscience. 2015 Jun 4;295:139-50. doi: 10.1016/j.neuroscience.2015.03.026. Epub 2015 Mar 20.
• [10] PCMT1 Ameliorates Neuronal Apoptosis by Inhibiting the Activation of MST1 after Subarachnoid Hemorrhage in Rats.Transl Stroke Res. 2017 May 22. doi: 10.1007/s12975-017-0540-8. Online ahead of print.
• [11] Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase?.Diabetologia. 2007 Mar;50(3):676-81. doi: 10.1007/s00125-006-0556-1. Epub 2007 Jan 10.
• [12] 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.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] 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.
• [17] Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells. Neuroscience. 2014 May 16;267:263-76. doi: 10.1016/j.neuroscience.2014.03.001. Epub 2014 Mar 12.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] 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.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [24] Proteomic analysis reveals multiple patterns of response in cells exposed to a toxin mixture. Chem Res Toxicol. 2009 Jun;22(6):1077-85.