Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVXPA9E)

• DOT Name: Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1)
• Synonyms: EC 2.4.1.142; Asparagine-linked glycosylation protein 1 homolog; Beta-1,4-mannosyltransferase; GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase; GDP-mannose-dolichol diphosphochitobiose mannosyltransferase; Mannosyltransferase-1; MT-1; hMat-1
• Gene Name: ALG1
• Related Disease:
  ALG1-congenital disorder of glycosylation
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Amyotrophic lateral sclerosis type 1
  Classic Hodgkin lymphoma
  Colonic neoplasm
  Creutzfeldt Jacob disease
  Graves disease
  Laryngeal carcinoma
  Laryngeal squamous cell carcinoma
  Lymphosarcoma
  Malignant pleural mesothelioma
  Methionine adenosyltransferase deficiency
  Nephritis
  Non-immune hydrops fetalis
  Schizophrenia
  Lung cancer
  Lung carcinoma
  Lupus nephritis
  Non-small-cell lung cancer
  Congenital disorder of glycosylation
  Hepatocellular carcinoma
  Muscular dystrophy-dystroglycanopathy, type A
  Non-insulin dependent diabetes
  Stroke
  Systemic lupus erythematosus
• UniProt ID: ALG1_HUMAN
• EC Number: 2.4.1.142
• Pfam ID: PF00534
• Sequence:
  MAASCLVLLALCLLLPLLLLGGWKRWRRGRAARHVVAVVLGDVGRSPRMQYHALSLAMHG
  FSVTLLGFCNSKPHDELLQNNRIQIVGLTELQSLAVGPRVFQYGVKVVLQAMYLLWKLMW
  REPGAYIFLQNPPGLPSIAVCWFVGCLCGSKLVIDWHNYGYSIMGLVHGPNHPLVLLAKW
  YEKFFGRLSHLNLCVTNAMREDLADNWHIRAVTVYDKPASFFKETPLDLQHRLFMKLGSM
  HSPFRARSEPEDPVTERSAFTERDAGSGLVTRLRERPALLVSSTSWTEDEDFSILLAALE
  KFEQLTLDGHNLPSLVCVITGKGPLREYYSRLIHQKHFQHIQVCTPWLEAEDYPLLLGSA
  DLGVCLHTSSSGLDLPMKVVDMFGCCLPVCAVNFKCLHELVKHEENGLVFEDSEELAAQL
  QMLFSNFPDPAGKLNQFRKNLRESQQLRWDESWVQTVLPLVMDT
• Function: Catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG1 causes CDG-1k (R-HSA-4549380)
  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

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ALG1-congenital disorder of glycosylation	DISOX57C	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	Strong	Biomarker	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[5]
Colonic neoplasm	DISSZ04P	Strong	Posttranslational Modification	[6]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[7]
Graves disease	DISU4KOQ	Strong	Biomarker	[8]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[9]
Laryngeal squamous cell carcinoma	DIS9UUVF	Strong	Biomarker	[9]
Lymphosarcoma	DISGYV3F	Strong	Posttranslational Modification	[10]
Malignant pleural mesothelioma	DIST2R60	Strong	Biomarker	[3]
Methionine adenosyltransferase deficiency	DIS4SI69	Strong	Genetic Variation	[11]
Nephritis	DISQZQ70	Strong	Altered Expression	[12]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[15]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[15]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[12]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[16]
Congenital disorder of glycosylation	DIS400QP	Limited	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[17]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Limited	Genetic Variation	[18]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[19]
Stroke	DISX6UHX	Limited	Biomarker	[20]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[12]

3 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 Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[21]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1).	[26]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] A case-control study of Metallothionein-1 expression in breast cancer and breast fibroadenoma.Sci Rep. 2019 May 15;9(1):7407. doi: 10.1038/s41598-019-43565-0.
• [3] Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy.Oncotarget. 2018 Apr 27;9(32):22254-22268. doi: 10.18632/oncotarget.24962. eCollection 2018 Apr 27.
• [4] Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner.Eur J Neurosci. 2001 Apr;13(7):1363-70. doi: 10.1046/j.0953-816x.2001.01512.x.
• [5] A novel MspI PCR-RFLP in the human cytosine 5-methyltransferase gene: lack of relevance for malignant lymphoproliferative disease and breast cancer.Hum Hered. 1998 Jul-Aug;48(4):226-9. doi: 10.1159/000022805.
• [6] Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line.Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495-9. doi: 10.1073/pnas.89.10.4495.
• [7] Differential expression of metallothioneins in human prion diseases.Dement Geriatr Cogn Disord. 2000 Sep-Oct;11(5):251-62. doi: 10.1159/000017247.
• [8] Expression of Metallothionein I/II and Ki-67 Antigen in Graves' Disease.Anticancer Res. 2018 Dec;38(12):6847-6853. doi: 10.21873/anticanres.13059.
• [9] Potential biomarkers for head and neck squamous cell carcinoma.Laryngoscope. 2003 Mar;113(3):393-400. doi: 10.1097/00005537-200303000-00001.
• [10] Physical and functional interaction of DNA methyltransferase 3A with Mbd3 and Brg1 in mouse lymphosarcoma cells.Cancer Res. 2005 Dec 1;65(23):10891-900. doi: 10.1158/0008-5472.CAN-05-1455.
• [11] Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency. J Clin Invest. 1996 Aug 15;98(4):1021-7. doi: 10.1172/JCI118862.
• [12] The renal metallothionein expression profile is altered in human lupus nephritis.Arthritis Res Ther. 2008;10(4):R76. doi: 10.1186/ar2450. Epub 2008 Jul 6.
• [13] Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review.J Inherit Metab Dis. 2020 Mar;43(2):223-233. doi: 10.1002/jimd.12162. Epub 2019 Nov 8.
• [14] Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population.PLoS One. 2018 Jan 8;13(1):e0190991. doi: 10.1371/journal.pone.0190991. eCollection 2018.
• [15] Impact of metallothionein gene polymorphisms on the risk of lung cancer in a Japanese population.Mol Carcinog. 2015 Jun;54 Suppl 1:E122-8. doi: 10.1002/mc.22198. Epub 2014 Aug 30.
• [16] Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients.Exp Mol Pathol. 2013 Feb;94(1):301-8. doi: 10.1016/j.yexmp.2012.10.006. Epub 2012 Oct 9.
• [17] Prognostic Significance of 14-3-3, Aldo-keto Reductase Family 1 B10 and Metallothionein-1 in Hepatocellular Carcinoma.Anticancer Res. 2018 Dec;38(12):6855-6863. doi: 10.21873/anticanres.13060.
• [18] POMT1 mutation results in defective glycosylation and loss of laminin-binding activity in alpha-DG.Neurology. 2004 Mar 23;62(6):1009-11. doi: 10.1212/01.wnl.0000115386.28769.65.
• [19] Metallothionein-mediated antioxidant defense system and its response to exercise training are impaired in human type 2 diabetes.Diabetes. 2005 Nov;54(11):3089-94. doi: 10.2337/diabetes.54.11.3089.
• [20] Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke.FASEB J. 2018 May;32(5):2381-2394. doi: 10.1096/fj.201700746R. Epub 2017 Dec 21.
• [21] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] 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.
• [24] 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.
• [25] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.