Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9N1DK3)

• DOT Name: Beta-glucuronidase (GUSB)
• Synonyms: EC 3.2.1.31; Beta-G1
• Gene Name: GUSB
• Related Disease: Mucopolysaccharidosis type 7
• UniProt ID: BGLR_HUMAN
• PDB ID: 1BHG; 3HN3
• EC Number: 3.2.1.31
• Pfam ID: PF00703 ; PF02836 ; PF02837
• Sequence:
  MARGSAVAWAALGPLLWGCALGLQGGMLYPQESPSRECKELDGLWSFRADFSDNRRRGFE
  EQWYRRPLWESGPTVDMPVPSSFNDISQDWRLRHFVGWVWYEREVILPERWTQDLRTRVV
  LRIGSAHSYAIVWVNGVDTLEHEGGYLPFEADISNLVQVGPLPSRLRITIAINNTLTPTT
  LPPGTIQYLTDTSKYPKGYFVQNTYFDFFNYAGLQRSVLLYTTPTTYIDDITVTTSVEQD
  SGLVNYQISVKGSNLFKLEVRLLDAENKVVANGTGTQGQLKVPGVSLWWPYLMHERPAYL
  YSLEVQLTAQTSLGPVSDFYTLPVGIRTVAVTKSQFLINGKPFYFHGVNKHEDADIRGKG
  FDWPLLVKDFNLLRWLGANAFRTSHYPYAEEVMQMCDRYGIVVIDECPGVGLALPQFFNN
  VSLHHHMQVMEEVVRRDKNHPAVVMWSVANEPASHLESAGYYLKMVIAHTKSLDPSRPVT
  FVSNSNYAADKGAPYVDVICLNSYYSWYHDYGHLELIQLQLATQFENWYKKYQKPIIQSE
  YGAETIAGFHQDPPLMFTEEYQKSLLEQYHLGLDQKRRKYVVGELIWNFADFMTEQSPTR
  VLGNKKGIFTRQRQPKSAAFLLRERYWKIANETRYPHSVAKSQCLENSLFT
• Function: Plays an important role in the degradation of dermatan and keratan sulfates.
• KEGG Pathway:
  Pentose and glucuro.te interconversions (hsa00040)
  Ascorbate and aldarate metabolism (hsa00053)
  Glycosaminoglycan degradation (hsa00531)
  Porphyrin metabolism (hsa00860)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Lysosome (hsa04142)
• Reactome Pathway:
  Hyaluronan uptake and degradation (R-HSA-2160916)
  MPS VII - Sly syndrome (R-HSA-2206292)
  Neutrophil degranulation (R-HSA-6798695)
  HS-GAG degradation (R-HSA-2024096)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mucopolysaccharidosis type 7	DISTF41F	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Beta-glucuronidase (GUSB) affects the response to substance of Paclitaxel.	[16]
Vinblastine	DM5TVS3	Approved	Beta-glucuronidase (GUSB) affects the response to substance of Vinblastine.	[16]
Captopril	DM458UM	Approved	Beta-glucuronidase (GUSB) increases the Leukopenia ADR of Captopril.	[17]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Beta-glucuronidase (GUSB).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Beta-glucuronidase (GUSB).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-glucuronidase (GUSB).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-glucuronidase (GUSB).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-glucuronidase (GUSB).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-glucuronidase (GUSB).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Beta-glucuronidase (GUSB).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Beta-glucuronidase (GUSB).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Beta-glucuronidase (GUSB).	[9]
Ergotidine	DM78IME	Approved	Ergotidine increases the expression of Beta-glucuronidase (GUSB).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Beta-glucuronidase (GUSB).	[12]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Beta-glucuronidase (GUSB).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Beta-glucuronidase (GUSB).	[14]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benoxaprofen	DM5ZOX8	Withdrawn from market	Benoxaprofen increases the secretion of Beta-glucuronidase (GUSB).	[13]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the secretion of Beta-glucuronidase (GUSB).	[15]

References

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• [2] 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.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [10] Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol. 2001 Mar 15;166(6):4083-91.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] 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.
• [13] Effects of benoxaprofen on human neutrophil function. J Rheumatol. 1984 Jun;11(3):265-71.
• [14] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] Differential regulation of neutrophil phospholipase d activity and degranulation. Biochem Biophys Res Commun. 2002 Apr 12;292(4):951-6. doi: 10.1006/bbrc.2002.6765.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [17] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.