Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI780UB)

• DOT Name: Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1)
• Synonyms: EC 3.2.1.113; ER alpha-1,2-mannosidase; ER mannosidase 1; ERMan1; Man9GlcNAc2-specific-processing alpha-mannosidase; Mannosidase alpha class 1B member 1
• Gene Name: MAN1B1
• Related Disease:
  MAN1B1-congenital disorder of glycosylation
  Advanced cancer
  ALG2-congenital disorder of glycosylation
  Alpha-1 antitrypsin deficiency
  Bladder cancer
  Congenital disorder of glycosylation
  Hepatocellular carcinoma
  Intellectual disability
  Pelvic inflammatory disease
  Rafiq syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: MA1B1_HUMAN
• PDB ID: 1FMI; 1FO2; 1FO3; 1X9D; 5KIJ; 5KK7
• EC Number: 3.2.1.113
• Pfam ID: PF01532
• Sequence:
  MAACEGRRSGALGSSQSDFLTPPVGGAPWAVATTVVMYPPPPPPPHRDFISVTLSFGENY
  DNSKSWRRRSCWRKWKQLSRLQRNMILFLLAFLLFCGLLFYINLADHWKALAFRLEEEQK
  MRPEIAGLKPANPPVLPAPQKADTDPENLPEISSQKTQRHIQRGPPHLQIRPPSQDLKDG
  TQEEATKRQEAPVDPRPEGDPQRTVISWRGAVIEPEQGTELPSRRAEVPTKPPLPPARTQ
  GTPVHLNYRQKGVIDVFLHAWKGYRKFAWGHDELKPVSRSFSEWFGLGLTLIDALDTMWI
  LGLRKEFEEARKWVSKKLHFEKDVDVNLFESTIRILGGLLSAYHLSGDSLFLRKAEDFGN
  RLMPAFRTPSKIPYSDVNIGTGVAHPPRWTSDSTVAEVTSIQLEFRELSRLTGDKKFQEA
  VEKVTQHIHGLSGKKDGLVPMFINTHSGLFTHLGVFTLGARADSYYEYLLKQWIQGGKQE
  TQLLEDYVEAIEGVRTHLLRHSEPSKLTFVGELAHGRFSAKMDHLVCFLPGTLALGVYHG
  LPASHMELAQELMETCYQMNRQMETGLSPEIVHFNLYPQPGRRDVEVKPADRHNLLRPET
  VESLFYLYRVTGDRKYQDWGWEILQSFSRFTRVPSGGYSSINNVQDPQKPEPRDKMESFF
  LGETLKYLFLLFSDDPNLLSLDAYVFNTEAHPLPIWTPA
• Function: Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2).
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  ER Quality Control Compartment (ERQC) (R-HSA-901032)
  Maturation of spike protein (R-HSA-9694548)
  Defective MAN1B1 causes MRT15 (R-HSA-4793950)
• BioCyc Pathway: MetaCyc:HS11144-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
MAN1B1-congenital disorder of glycosylation	DIS8VNJ8	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
ALG2-congenital disorder of glycosylation	DISIVO8V	Strong	Biomarker	[3]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Pelvic inflammatory disease	DISWQR4J	Strong	Altered Expression	[7]
Rafiq syndrome	DIS8I1SW	Strong	Autosomal recessive	[8]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[15]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase (MAN1B1).	[16]

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] ERManI is a target of miR-125b and promotes transformation phenotypes in hepatocellular carcinoma (HCC).PLoS One. 2013 Aug 5;8(8):e72829. doi: 10.1371/journal.pone.0072829. Print 2013.
• [3] Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. Brain. 2014 Apr;137(Pt 4):1030-8. doi: 10.1093/brain/awu019. Epub 2014 Feb 24.
• [4] SERPINA1 and MAN1B1 polymorphisms are not linked to severe liver disease in a French cohort of alpha-1 antitrypsin deficiency children.Liver Int. 2017 Nov;37(11):1608-1611. doi: 10.1111/liv.13586. Epub 2017 Sep 15.
• [5] MAN1B1 is associated with poor prognosis and modulates proliferation and apoptosis in bladder cancer.Gene. 2018 Dec 30;679:314-319. doi: 10.1016/j.gene.2018.09.022. Epub 2018 Sep 12.
• [6] MAN1B-CDG: Novel variants with a distinct phenotype and review of literature.Eur J Med Genet. 2019 Feb;62(2):109-114. doi: 10.1016/j.ejmg.2018.06.011. Epub 2018 Jun 14.
• [7] Increased activity of lysosomal enzymes in the peritoneal fluid of patients with gynecologic cancers and pelvic inflammatory disease.J Cancer Res Clin Oncol. 2005 Jun;131(6):371-6. doi: 10.1007/s00432-004-0649-5. Epub 2005 Mar 23.
• [8] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [9] Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2011 Jul 15;89(1):176-82. doi: 10.1016/j.ajhg.2011.06.006.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [14] 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.
• [15] 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.
• [16] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.