Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBSR6DT)

• DOT Name: Alpha-galactosidase A (GLA)
• Synonyms: EC 3.2.1.22; Alpha-D-galactosidase A; Alpha-D-galactoside galactohydrolase; Galactosylgalactosylglucosylceramidase GLA; Melibiase; Agalsidase
• Gene Name: GLA
• Related Disease: Fabry disease
• UniProt ID: AGAL_HUMAN
• PDB ID: 1R46; 1R47; 3GXN; 3GXP; 3GXT; 3HG2; 3HG3; 3HG4; 3HG5; 3LX9; 3LXA; 3LXB; 3LXC; 3S5Y; 3S5Z; 3TV8; 4NXS; 6IBK; 6IBM; 6IBR; 6IBT
• EC Number: 3.2.1.22
• Pfam ID: PF16499 ; PF17450
• Sequence:
  MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEP
  DSCISEKLFMEMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQL
  ANYVHSKGLKLGIYADVGNKTCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENL
  ADGYKHMSLALNRTGRSIVYSCEWPLYMWPFQKPNYTEIRQYCNHWRNFADIDDSWKSIK
  SILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQVTQMALWAIMAAPLFMSNDL
  RHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWAVAMINRQEIG
  GPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT
  MQMSLKDLL
• Function: Catalyzes the hydrolysis of glycosphingolipids and participates in their degradation in the lysosome.
• KEGG Pathway:
  Galactose metabolism (hsa00052)
  Glycerolipid metabolism (hsa00561)
  Sphingolipid metabolism (hsa00600)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Glycosphingolipid catabolism (R-HSA-9840310)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS02389-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fabry disease	DISUUQJF	Definitive	X-linked	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Alpha-galactosidase A (GLA) affects the response to substance of Fluorouracil.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Alpha-galactosidase A (GLA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-galactosidase A (GLA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-galactosidase A (GLA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-galactosidase A (GLA).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-galactosidase A (GLA).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Alpha-galactosidase A (GLA).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-galactosidase A (GLA).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Alpha-galactosidase A (GLA).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Alpha-galactosidase A (GLA).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Alpha-galactosidase A (GLA).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Alpha-galactosidase A (GLA).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Alpha-galactosidase A (GLA).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Alpha-galactosidase A (GLA).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Alpha-galactosidase A (GLA).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Alpha-galactosidase A (GLA).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Alpha-galactosidase A (GLA).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Alpha-galactosidase A (GLA).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-galactosidase A (GLA).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Alpha-galactosidase A (GLA).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alpha-galactosidase A (GLA).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alpha-galactosidase A (GLA).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Alpha-galactosidase A (GLA).	[22]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Alpha-galactosidase A (GLA).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Alpha-galactosidase A (GLA).	[24]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Alpha-galactosidase A (GLA).	[10]

References

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• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
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• [10] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] 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.
• [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] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [25] 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.