Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT86XWU2)

• DOT Name: Cytosolic beta-glucosidase (GBA3)
• Synonyms: EC 3.2.1.21; Cytosolic beta-glucosidase-like protein 1; Cytosolic galactosylceramidase; EC 3.2.1.46; Cytosolic glucosylceramidase; EC 3.2.1.45; Cytosolic glycosylceramidase; Cytosolic GCase; Glucosidase beta acid 3; Glucosylceramidase beta 3; Klotho-related protein; KLrP
• Gene Name: GBA3
• Related Disease:
  Hepatocellular carcinoma
  Anca-associated vasculitis
  Cushing disease
  Cystic fibrosis
  Drug dependence
  Gastric cancer
  Gaucher disease
  Gaucher disease type I
  Stomach cancer
  Substance abuse
  Substance dependence
  Neuroendocrine neoplasm
  Stroke
  Type-1 diabetes
• UniProt ID: GBA3_HUMAN
• PDB ID: 2E9L; 2E9M; 2JFE; 2ZOX; 3VKK
• EC Number: 3.2.1.21; 3.2.1.45; 3.2.1.46
• Pfam ID: PF00232
• Sequence:
  MAFPAGFGWAAATAAYQVEGGWDADGKGPCVWDTFTHQGGERVFKNQTGDVACGSYTLWE
  EDLKCIKQLGLTHYRFSLSWSRLLPDGTTGFINQKGIDYYNKIIDDLLKNGVTPIVTLYH
  FDLPQTLEDQGGWLSEAIIESFDKYAQFCFSTFGDRVKQWITINEANVLSVMSYDLGMFP
  PGIPHFGTGGYQAAHNLIKAHARSWHSYDSLFRKKQKGMVSLSLFAVWLEPADPNSVSDQ
  EAAKRAITFHLDLFAKPIFIDGDYPEVVKSQIASMSQKQGYPSSRLPEFTEEEKKMIKGT
  ADFFAVQYYTTRLIKYQENKKGELGILQDAEIEFFPDPSWKNVDWIYVVPWGVCKLLKYI
  KDTYNNPVIYITENGFPQSDPAPLDDTQRWEYFRQTFQELFKAIQLDKVNLQVYCAWSLL
  DNFEWNQGYSSRFGLFHVDFEDPARPRVPYTSAKEYAKIIRNNGLEAHL
• Function: Neutral cytosolic beta-glycosidase with a broad substrate specificity that could play a role in the catabolism of glycosylceramides. Has a significant glucosylceramidase activity in vitro. However, that activity is relatively low and its significance in vivo is not clear. Hydrolyzes galactosylceramides/GalCers, glucosylsphingosines/GlcSphs and galactosylsphingosines/GalSphs. However, the in vivo relevance of these activities is unclear. It can also hydrolyze a broad variety of dietary glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens in vitro and could therefore play a role in the metabolism of xenobiotics. Possesses transxylosylase activity in vitro using xylosylated ceramides/XylCers (such as beta-D-xylosyl-(1<->1')-N-acylsphing-4-enine) as xylosyl donors and cholesterol as acceptor. Could also play a role in the catabolism of cytosolic sialyl free N-glycans.
• Tissue Specificity: Present in small intestine (at protein level). Expressed in liver, small intestine, colon, spleen and kidney. Down-regulated in renal cell carcinomas and hepatocellular carcinomas.
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)
• BioCyc Pathway: MetaCyc:HS11014-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Anca-associated vasculitis	DISU3CNU	Strong	Genetic Variation	[2]
Cushing disease	DISOG6P2	Strong	Biomarker	[3]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Gaucher disease	DISTW5JG	Strong	Biomarker	[7]
Gaucher disease type I	DIS87KKY	Strong	Genetic Variation	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Neuroendocrine neoplasm	DISNPLOO	Limited	Biomarker	[8]
Stroke	DISX6UHX	Limited	Altered Expression	[9]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[10]

2 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 Cytosolic beta-glucosidase (GBA3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Cytosolic beta-glucosidase (GBA3).	[19]

10 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 Cytosolic beta-glucosidase (GBA3).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytosolic beta-glucosidase (GBA3).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic beta-glucosidase (GBA3).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytosolic beta-glucosidase (GBA3).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cytosolic beta-glucosidase (GBA3).	[15]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Cytosolic beta-glucosidase (GBA3).	[15]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Cytosolic beta-glucosidase (GBA3).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Cytosolic beta-glucosidase (GBA3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytosolic beta-glucosidase (GBA3).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Cytosolic beta-glucosidase (GBA3).	[20]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] A linkage disequilibrium between genes at the serine protease inhibitor gene cluster on chromosome 14q32.1 is associated with Wegener's granulomatosis.Clin Immunol. 2001 Feb;98(2):244-8. doi: 10.1006/clim.2000.4962.
• [3] LONG-TERM OUTCOME OF THE DIFFERENT TREATMENT ALTERNATIVES FOR RECURRENT AND PERSISTENT CUSHING DISEASE.Endocr Pract. 2017 Jul;23(7):759-767. doi: 10.4158/EP171756.OR. Epub 2017 Mar 23.
• [4] Opposite Expression of Hepatic and Pulmonary Corticosteroid-Binding Globulin in Cystic Fibrosis Patients.Front Pharmacol. 2018 Jun 5;9:545. doi: 10.3389/fphar.2018.00545. eCollection 2018.
• [5] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [6] Co-Expression of NEU2 and GBA3 Causes a Drastic Reduction in Cytosolic Sialyl Free N-glycans in Human MKN45 Stomach Cancer Cells-Evidence for the Physical Interaction of NEU2 and GBA3.Biomolecules. 2015 Jul 16;5(3):1499-514. doi: 10.3390/biom5031499.
• [7] The cytosolic -glucosidase GBA3 does not influence type 1 Gaucher disease manifestation.Blood Cells Mol Dis. 2011 Jan 15;46(1):19-26. doi: 10.1016/j.bcmd.2010.07.009. Epub 2010 Aug 21.
• [8] AN INDIVIDUALIZED APPROACH TO THE EVALUATION OF CUSHING SYNDROME.Endocr Pract. 2017 Jun;23(6):726-737. doi: 10.4158/EP161721.RA.
• [9] High-throughput profiling of the circulating proteome suggests sexually dimorphic corticosteroid signaling following ischemic stroke.Physiol Genomics. 2018 Oct 1;50(10):876-883. doi: 10.1152/physiolgenomics.00058.2018. Epub 2018 Jul 20.
• [10] Proportion of daily capillary blood glucose readings required in the target range for target glycaemic control: shift of focus from target range to proportion in range.Diabet Med. 2017 Oct;34(10):1456-1460. doi: 10.1111/dme.13438. Epub 2017 Aug 15.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] 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.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.