Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT27UPHN)

• DOT Name: Mannose-P-dolichol utilization defect 1 protein (MPDU1)
• Synonyms: Suppressor of Lec15 and Lec35 glycosylation mutation homolog; SL15
• Gene Name: MPDU1
• Related Disease:
  SRD5A3-congenital disorder of glycosylation
  Congenital disorder of glycosylation
  IgA nephropathy
  MPDU1-congenital disorder of glycosylation
  ALG3-congenital disorder of glycosylation
  Non-syndromic ichthyosis
  Neoplasm
• UniProt ID: MPU1_HUMAN
• Pfam ID: PF04193
• Sequence:
  MAAEADGPLKRLLVPILLPEKCYDQLFVQWDLLHVPCLKILLSKGLGLGIVAGSLLVKLP
  QVFKILGAKSAEGLSLQSVMLELVALTGTMVYSITNNFPFSSWGEALFLMLQTITICFLV
  MHYRGQTVKGVAFLACYGLVLLVLLSPLTPLTVVTLLQASNVPAVVVGRLLQAATNYHNG
  HTGQLSAITVFLLFGGSLARIFTSIQETGDPLMAGTFVVSSLCNGLIAAQLLFYWNAKPP
  HKQKKAQ
• Function: Required for normal utilization of mannose-dolichol phosphate (Dol-P-Man) in the synthesis of N-linked and O-linked oligosaccharides and GPI anchors.
• Reactome Pathway:
  Defective MPDU1 causes CDG-1f (R-HSA-4687000)
  Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein (R-HSA-446193)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
SRD5A3-congenital disorder of glycosylation	DISGHPPC	Definitive	Autosomal recessive	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[2]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[3]
MPDU1-congenital disorder of glycosylation	DISE7M0S	Strong	Autosomal recessive	[4]
ALG3-congenital disorder of glycosylation	DISDBRL6	moderate	Biomarker	[5]
Non-syndromic ichthyosis	DISZ9QBQ	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]

11 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 Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mannose-P-dolichol utilization defect 1 protein (MPDU1).	[18]

References

• [1] A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If). J Clin Invest. 2001 Dec;108(11):1613-9. doi: 10.1172/JCI13635.
• [2] Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center.J Pediatr (Rio J). 2020 Nov-Dec;96(6):710-716. doi: 10.1016/j.jped.2019.05.008. Epub 2019 Oct 31.
• [3] A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy.Nat Genet. 2011 Dec 25;44(2):178-82. doi: 10.1038/ng.1047.
• [4] MPDU1 mutations underlie a novel human congenital disorder of glycosylation, designated type If. J Clin Invest. 2001 Dec;108(11):1687-95. doi: 10.1172/JCI13419.
• [5] Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts.Glycobiology. 2005 Nov;15(11):1084-93. doi: 10.1093/glycob/cwj006. Epub 2005 Aug 3.
• [6] Severe ichthyosis in MPDU1-CDG.J Inherit Metab Dis. 2018 Nov;41(6):1293-1294. doi: 10.1007/s10545-018-0189-9. Epub 2018 May 2.
• [7] Differential gene expression profiling linked to tumor progression of splenic marginal zone lymphoma.Sci Rep. 2017 Sep 8;7(1):11026. doi: 10.1038/s41598-017-11389-5.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] 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.
• [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] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.