Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPOL1QW)

• DOT Name: Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3)
• Synonyms: EC 2.4.1.258; Asparagine-linked glycosylation protein 3 homolog; Dol-P-Man-dependent alpha(1-3)-mannosyltransferase; Dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase; Dolichyl-phosphate-mannose--glycolipid alpha-mannosyltransferase; Not56-like protein
• Gene Name: ALG3
• Related Disease:
  ALG3-congenital disorder of glycosylation
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Congenital disorder of glycosylation
  Developmental and epileptic encephalopathy, 36
  Esophageal squamous cell carcinoma
  Familial Alzheimer disease
  Neoplasm
  Head-neck squamous cell carcinoma
  Laryngeal squamous cell carcinoma
  MPDU1-congenital disorder of glycosylation
• UniProt ID: ALG3_HUMAN
• EC Number: 2.4.1.258
• Pfam ID: PF05208
• Sequence:
  MAAGLRKRGRSGSAAQAEGLCKQWLQRAWQERRLLLREPRYTLLVAACLCLAEVGITFWV
  IHRVAYTEIDWKAYMAEVEGVINGTYDYTQLQGDTGPLVYPAGFVYIFMGLYYATSRGTD
  IRMAQNIFAVLYLATLLLVFLIYHQTCKVPPFVFFFMCCASYRVHSIFVLRLFNDPVAMV
  LLFLSINLLLAQRWGWGCCFFSLAVSVKMNVLLFAPGLLFLLLTQFGFRGALPKLGICAG
  LQVVLGLPFLLENPSGYLSRSFDLGRQFLFHWTVNWRFLPEALFLHRAFHLALLTAHLTL
  LLLFALCRWHRTGESILSLLRDPSKRKVPPQPLTPNQIVSTLFTSNFIGICFSRSLHYQF
  YVWYFHTLPYLLWAMPARWLTHLLRLLVLGLIELSWNTYPSTSCSSAALHICHAVILLQL
  WLGPQPFPKSTQHSKKAH
• Function: Adds the first Dol-P-Man derived mannose in an alpha-1,3 linkage to Man5GlcNAc2-PP-Dol.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG3 causes CDG-1d (R-HSA-4720475)
  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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ALG3-congenital disorder of glycosylation	DISDBRL6	Definitive	Autosomal recessive	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[5]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[3]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[3]
MPDU1-congenital disorder of glycosylation	DISE7M0S	moderate	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[13]
Epanova	DMHEAGL	Approved	Epanova decreases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (ALG3).	[15]

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] Aberrant mannosylation profile and FTX/miR-342/ALG3-axis contribute to development of drug resistance in acute myeloid leukemia.Cell Death Dis. 2018 Jun 7;9(6):688. doi: 10.1038/s41419-018-0706-7.
• [3] Combined expression and prognostic significance of PPFIA1 and ALG3 in head and neck squamous cell carcinoma.Mol Biol Rep. 2019 Jun;46(3):2693-2701. doi: 10.1007/s11033-019-04712-y. Epub 2019 Feb 25.
• [4] ALG3 Is Activated by Heat Shock Factor 2 and Promotes Breast Cancer Growth.Med Sci Monit. 2018 May 25;24:3479-3487. doi: 10.12659/MSM.907461.
• [5] Novel variants and clinical symptoms in four new ALG3-CDG patients, review of the literature, and identification of AAGRP-ALG3 as a novel ALG3 variant with alanine and glycine-rich N-terminus. Hum Mutat. 2019 Jul;40(7):938-951. doi: 10.1002/humu.23764. Epub 2019 May 8.
• [6] Identification of putative target genes for amplification within 11q13.2 and 3q27.1 in esophageal squamous cell carcinoma.Clin Transl Oncol. 2014 Jul;16(7):606-15. doi: 10.1007/s12094-013-1124-z. Epub 2013 Nov 8.
• [7] Functional cloning of genes involved in T-cell receptor-induced programmed cell death.Semin Immunol. 1997 Feb;9(1):17-23. doi: 10.1006/smim.1996.0057.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [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.