Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5TS6P7)

• DOT Name: Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1)
• Gene Name: PCMTD1
• Related Disease:
  Angle-closure glaucoma
  Major depressive disorder
  Primary angle-closure glaucoma
  Venous thromboembolism
• UniProt ID: PCMD1_HUMAN
• Pfam ID: PF01135
• Sequence:
  MGGAVSAGEDNDDLIDNLKEAQYIRTERVEQAFRAIDRGDYYLEGYRDNAYKDLAWKHGN
  IHLSAPCIYSEVMEALKLQPGLSFLNLGSGTGYLSTMVGLILGPFGINHGIELHSDVVEY
  AKEKLESFIKNSDSFDKFEFCEPAFVVGNCLQIASDSHQYDRIYCGAGVQKDHENYMKIL
  LKVGGILVMPIEDQLTQIMRTGQNTWESKNILAVSFAPLVQPSKNDNGKPDSVGLPPCAV
  RNLQDLARIYIRRTLRNFINDEMQAKGIPQRAPPKRKRKRVKQRINTYVFVGNQLIPQPL
  DSEEDEKMEEDNKEEEEKDHNEAMKPEEPPQNLLREKIMKLPLPESLKAYLTYFRDK
• Function: Substrate recognition component of an ECS (Elongin BC-CUL5-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Specifically binds to the methyltransferase cofactor S-adenosylmethionine (AdoMet) via the N-terminal AdoMet binding motif, but does not display methyltransferase activity. May provide an alternate maintenance pathway for modified proteins by acting as a damage-specific E3 ubiquitin ligase adaptor protein.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[1]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[2]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Genetic Variation	[1]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[10]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[14]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[20]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein-L-isoaspartate O-methyltransferase domain-containing protein 1 (PCMTD1).	[18]

References

• [1] Integration of Genetic and Biometric Risk Factors for Detection of Primary Angle Closure Glaucoma.Am J Ophthalmol. 2019 Dec;208:160-165. doi: 10.1016/j.ajo.2019.07.022. Epub 2019 Aug 1.
• [2] Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.Nat Genet. 2016 Sep;48(9):1031-6. doi: 10.1038/ng.3623. Epub 2016 Aug 1.
• [3] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [16] 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.
• [17] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.