Details of Drug Off-Target (DOT)

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

• DOT Name: Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2)
• Synonyms: Dolichol-phosphate mannose synthase subunit 2; DPM synthase subunit 2
• Gene Name: DPM2
• Related Disease:
  Angle-closure glaucoma
  Congenital disorder of glycosylation
  Congenital muscular dystrophy with intellectual disability and severe epilepsy
  Epilepsy
  Muscular dystrophy
  Primary angle-closure glaucoma
  Sarcoidosis
  Parkinsonian disorder
  Glaucoma/ocular hypertension
• UniProt ID: DPM2_HUMAN
• Pfam ID: PF07297
• Sequence:
  MATGTDQVVGLGLVAVSLIIFTYYTAWVILLPFIDSQHVIHKYFLPRAYAVAIPLAAGLL
  LLLFVGLFISYVMLKTKRVTKKAQ
• Function: Regulates the biosynthesis of dolichol phosphate-mannose. Regulatory subunit of the dolichol-phosphate mannose (DPM) synthase complex; essential for the ER localization and stable expression of DPM1. Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis. May act by regulating the GPI-GNT complex.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Glycosylphosphatidylinositol (GPI)-anchor biosynthesis (hsa00563)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of glycosylphosphatidylinositol (GPI) (R-HSA-162710)
  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:ENSG00000136908-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[2]
Congenital muscular dystrophy with intellectual disability and severe epilepsy	DIS2GJDS	Strong	Autosomal recessive	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[2]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Genetic Variation	[1]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[3]
Parkinsonian disorder	DISHGY45	Disputed	Biomarker	[4]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[5]

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 Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[11]

5 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 Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dolichol phosphate-mannose biosynthesis regulatory protein (DPM2).	[12]

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] DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. Ann Neurol. 2012 Oct;72(4):550-8. doi: 10.1002/ana.23632.
• [3] Search for sarcoidosis candidate genes by integration of data from genomic, transcriptomic and proteomic studies.Med Sci Monit. 2009 Dec;15(12):SR22-8.
• [4] Molecular hypotheses to explain the shared pathways and underlying pathobiological causes in catatonia and in catatonic presentations in neuropsychiatric disorders.Med Hypotheses. 2018 Apr;113:54-64. doi: 10.1016/j.mehy.2018.02.009. Epub 2018 Feb 15.
• [5] Genetics of glaucoma.Hum Mol Genet. 2017 Aug 1;26(R1):R21-R27. doi: 10.1093/hmg/ddx184.
• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] 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.
• [10] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [11] 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.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.