Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77B384)

• DOT Name: Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2)
• Synonyms: EC 2.4.1.132; EC 2.4.1.257; Asparagine-linked glycosylation protein 2 homolog; GDP-Man:Man(1)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase; GDP-Man:Man(1)GlcNAc(2)-PP-dolichol mannosyltransferase; GDP-Man:Man(2)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase
• Gene Name: ALG2
• Related Disease:
  Advanced cancer
  ALG2-congenital disorder of glycosylation
  Breast cancer
  Breast carcinoma
  Congenital disorder of glycosylation
  Congenital myasthenic syndrome
  Congenital myasthenic syndrome 14
  Obsolete congenital myasthenic syndromes with glycosylation defect
  Adult glioblastoma
  Glioblastoma multiforme
  Neoplasm
• UniProt ID: ALG2_HUMAN
• EC Number: 2.4.1.132; 2.4.1.257
• Pfam ID: PF13579 ; PF00534
• Sequence:
  MAEEQGRERDSVPKPSVLFLHPDLGVGGAERLVLDAALALQARGCSVKIWTAHYDPGHCF
  AESRELPVRCAGDWLPRGLGWGGRGAAVCAYVRMVFLALYVLFLADEEFDVVVCDQVSAC
  IPVFRLARRRKKILFYCHFPDLLLTKRDSFLKRLYRAPIDWIEEYTTGMADCILVNSQFT
  AAVFKETFKSLSHIDPDVLYPSLNVTSFDSVVPEKLDDLVPKGKKFLLLSINRYERKKNL
  TLALEALVQLRGRLTSQDWERVHLIVAGGYDERVLENVEHYQELKKMVQQSDLGQYVTFL
  RSFSDKQKISLLHSCTCVLYTPSNEHFGIVPLEAMYMQCPVIAVNSGGPLESIDHSVTGF
  LCEPDPVHFSEAIEKFIREPSLKATMGLAGRARVKEKFSPEAFTEQLYRYVTKLLV
• Function: Mannosylates Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG2 causes CDG-1i (R-HSA-4549349)
  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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
ALG2-congenital disorder of glycosylation	DISIVO8V	Strong	Autosomal recessive	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[4]
Congenital myasthenic syndrome	DISJLG2T	Strong	Genetic Variation	[5]
Congenital myasthenic syndrome 14	DIS5P72M	Strong	Autosomal recessive	[6]
Obsolete congenital myasthenic syndromes with glycosylation defect	DISIGACA	Supportive	Autosomal recessive	[7]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

1 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 Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[9]

11 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 Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alpha-1,3/1,6-mannosyltransferase ALG2 (ALG2).	[20]

References

• [1] ALG-2 participates in recovery of cells after plasma membrane damage by electroporation and digitonin treatment.PLoS One. 2018 Sep 21;13(9):e0204520. doi: 10.1371/journal.pone.0204520. eCollection 2018.
• [2] 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.
• [3] Apoptosis-linked gene 2 promotes breast cancer growth and metastasis by regulating the cytoskeleton.Oncotarget. 2017 Jan 10;8(2):2745-2757. doi: 10.18632/oncotarget.13740.
• [4] Ten years of screening for congenital disorders of glycosylation in Argentina: case studies and pitfalls.Pediatr Res. 2018 Dec;84(6):837-841. doi: 10.1038/s41390-018-0206-6. Epub 2018 Oct 18.
• [5] Trouble at the junction: When myopathy and myasthenia overlap.Muscle Nerve. 2019 Dec;60(6):648-657. doi: 10.1002/mus.26676. Epub 2019 Sep 10.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136(Pt 3):944-56. doi: 10.1093/brain/awt010. Epub 2013 Feb 11.
• [8] ALG2 regulates glioblastoma cell proliferation, migration and tumorigenicity.Biochem Biophys Res Commun. 2017 Apr 29;486(2):300-306. doi: 10.1016/j.bbrc.2017.03.032. Epub 2017 Mar 12.
• [9] 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.
• [10] 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.
• [11] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [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] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] 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.
• [16] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.