Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSB4XO0)

• DOT Name: Dolichol-phosphate mannosyltransferase subunit 3 (DPM3)
• Synonyms: Dolichol-phosphate mannose synthase subunit 3; DPM synthase subunit 3; Dolichyl-phosphate beta-D-mannosyltransferase subunit 3; Mannose-P-dolichol synthase subunit 3; MPD synthase subunit 3; Prostin-1
• Gene Name: DPM3
• Related Disease:
  Dilated cardiomyopathy
  DPM3-congenital disorder of glycosylation
  Prostate neoplasm
  Limb-girdle muscular dystrophy
  Cardiomyopathy
  Congenital disorder of glycosylation
• UniProt ID: DPM3_HUMAN
• Pfam ID: PF08285
• Sequence:
  MTKLAQWLWGLAILGSTWVALTTGALGLELPLSCQEVLWPLPAYLLVSAGCYALGTVGYR
  VATFHDCEDAARELQSQIQEARADLARRGLRF
• Function: Stabilizer subunit of the dolichol-phosphate mannose (DPM) synthase complex; tethers catalytic subunit DPM1 to the endoplasmic reticulum.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective DPM1 causes DPM1-CDG (R-HSA-4717374)
  Defective DPM3 causes DPM3-CDG (R-HSA-4719360)
  Defective DPM2 causes DPM2-CDG (R-HSA-4719377)
  Synthesis of dolichyl-phosphate mannose (R-HSA-162699)
• BioCyc Pathway: MetaCyc:ENSG00000179085-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dilated cardiomyopathy	DISX608J	Strong	Genetic Variation	[1]
DPM3-congenital disorder of glycosylation	DISCCM7R	Strong	Autosomal recessive	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Limb-girdle muscular dystrophy	DISI9Y1Z	moderate	Genetic Variation	[1]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[4]
Congenital disorder of glycosylation	DIS400QP	Limited	Biomarker	[5]

19 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 Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[16]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[10]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[10]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[22]

1 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 Dolichol-phosphate mannosyltransferase subunit 3 (DPM3).	[18]

References

• [1] Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene.Neuromuscul Disord. 2019 Jul;29(7):497-502. doi: 10.1016/j.nmd.2019.05.004. Epub 2019 May 9.
• [2] A recurrent homozygous missense DPM3 variant leads to muscle and brain disease. Clin Genet. 2022 Dec;102(6):530-536. doi: 10.1111/cge.14208. Epub 2022 Aug 19.
• [3] Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion.Oncogene. 2001 May 17;20(22):2781-90. doi: 10.1038/sj.onc.1204379.
• [4] A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy.Neuromuscul Disord. 2017 Nov;27(11):1043-1046. doi: 10.1016/j.nmd.2017.07.006. Epub 2017 Jul 17.
• [5] Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG.J Inherit Metab Dis. 2019 Sep;42(5):984-992. doi: 10.1002/jimd.12095. Epub 2019 Apr 23.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.