Details of Drug Off-Target (DOT)

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

• DOT Name: Dolichol-phosphate mannosyltransferase subunit 1 (DPM1)
• Synonyms: EC 2.4.1.83; Dolichol-phosphate mannose synthase subunit 1; DPM synthase subunit 1; Dolichyl-phosphate beta-D-mannosyltransferase subunit 1; Mannose-P-dolichol synthase subunit 1; MPD synthase subunit 1
• Gene Name: DPM1
• Related Disease:
  Congenital disorder of glycosylation type 1E
  SRD5A3-congenital disorder of glycosylation
  Congenital disorder of glycosylation
  Congenital muscular dystrophy
  Type-1/2 diabetes
• UniProt ID: DPM1_HUMAN
• EC Number: 2.4.1.83
• Pfam ID: PF00535
• Sequence:
  MASLEVSRSPRRSRRELEVRSPRQNKYSVLLPTYNERENLPLIVWLLVKSFSESGINYEI
  IIIDDGSPDGTRDVAEQLEKIYGSDRILLRPREKKLGLGTAYIHGMKHATGNYIIIMDAD
  LSHHPKFIPEFIRKQKEGNFDIVSGTRYKGNGGVYGWDLKRKIISRGANFLTQILLRPGA
  SDLTGSFRLYRKEVLEKLIEKCVSKGYVFQMEMIVRARQLNYTIGEVPISFVDRVYGESK
  LGGNEIVSFLKGLLTLFATT
• Function: Transfers mannose from GDP-mannose to dolichol monophosphate to form dolichol phosphate mannose (Dol-P-Man) which is the mannosyl donor in pathways leading to N-glycosylation, glycosyl phosphatidylinositol membrane anchoring, and O-mannosylation of proteins; catalytic subunit of the dolichol-phosphate mannose (DPM) synthase complex.
• 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:ENSG00000000419-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
Congenital disorder of glycosylation type 1E	DISWQLPO	Definitive	Autosomal recessive	[1]
SRD5A3-congenital disorder of glycosylation	DISGHPPC	Definitive	Autosomal recessive	[2]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[3]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[4]
Type-1/2 diabetes	DISIUHAP	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 decreases the methylation of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dolichol-phosphate mannosyltransferase subunit 1 (DPM1).	[17]

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] Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie). J Clin Invest. 2000 Jan;105(2):191-8. doi: 10.1172/JCI7302.
• [3] Structural basis for dolichylphosphate mannose biosynthesis.Nat Commun. 2017 Jul 25;8(1):120. doi: 10.1038/s41467-017-00187-2.
• [4] Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy. Mol Genet Metab. 2013 Nov;110(3):345-351. doi: 10.1016/j.ymgme.2013.06.016. Epub 2013 Jun 28.
• [5] Molecular property diagnostic suite for diabetes mellitus (MPDS(DM)): An integrated web portal for drug discovery and drug repurposing.J Biomed Inform. 2018 Sep;85:114-125. doi: 10.1016/j.jbi.2018.08.003. Epub 2018 Aug 6.
• [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] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [13] 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.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.