Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT48T897)

• DOT Name: Beta-hexosaminidase subunit alpha (HEXA)
• Synonyms: EC 3.2.1.52; Beta-N-acetylhexosaminidase subunit alpha; Hexosaminidase subunit A; N-acetyl-beta-glucosaminidase subunit alpha
• Gene Name: HEXA
• Related Disease: Tay-sachs disease
• UniProt ID: HEXA_HUMAN
• PDB ID: 2GJX; 2GK1
• EC Number: 3.2.1.52
• Pfam ID: PF00728 ; PF14845
• Sequence:
  MTSSRLWFSLLLAAAFAGRATALWPWPQNFQTSDQRYVLYPNNFQFQYDVSSAAQPGCSV
  LDEAFQRYRDLLFGSGSWPRPYLTGKRHTLEKNVLVVSVVTPGCNQLPTLESVENYTLTI
  NDDQCLLLSETVWGALRGLETFSQLVWKSAEGTFFINKTEIEDFPRFPHRGLLLDTSRHY
  LPLSSILDTLDVMAYNKLNVFHWHLVDDPSFPYESFTFPELMRKGSYNPVTHIYTAQDVK
  EVIEYARLRGIRVLAEFDTPGHTLSWGPGIPGLLTPCYSGSEPSGTFGPVNPSLNNTYEF
  MSTFFLEVSSVFPDFYLHLGGDEVDFTCWKSNPEIQDFMRKKGFGEDFKQLESFYIQTLL
  DIVSSYGKGYVVWQEVFDNKVKIQPDTIIQVWREDIPVNYMKELELVTKAGFRALLSAPW
  YLNRISYGPDWKDFYIVEPLAFEGTPEQKALVIGGEACMWGEYVDNTNLVPRLWPRAGAV
  AERLWSNKLTSDLTFAYERLSHFRCELLRRGVQAQPLNVGFCEQEFEQT
• Function: Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the oligosaccharide moieties from proteins and neutral glycolipids, or from certain mucopolysaccharides. The isozyme S is as active as the isozyme A on the anionic bis-sulfated glycans, the chondroitin-6-sulfate trisaccharide (C6S-3), and the dermatan sulfate pentasaccharide, and the sulfated glycosphingolipid SM2. The isozyme B does not hydrolyze each of these substrates, however hydrolyzes efficiently neutral oligosaccharide. Only the isozyme A is responsible for the degradation of GM2 gangliosides in the presence of GM2A.
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Various types of N-glycan biosynthesis (hsa00513)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Glycosaminoglycan degradation (hsa00531)
  Sphingolipid metabolism (hsa00600)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  CS/DS degradation (R-HSA-2024101)
  Hyaluronan uptake and degradation (R-HSA-2160916)
  Defective HEXA causes GM2G1 (R-HSA-3656234)
  Glycosphingolipid catabolism (R-HSA-9840310)
  Keratan sulfate degradation (R-HSA-2022857)
• BioCyc Pathway: MetaCyc:ENSG00000140495-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
Tay-sachs disease	DISWG5B4	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Beta-hexosaminidase subunit alpha (HEXA) increases the Nephropathy toxic ADR of Cisplatin.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Beta-hexosaminidase subunit alpha (HEXA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[6]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[9]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Beta-hexosaminidase subunit alpha (HEXA).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Beta-hexosaminidase subunit alpha (HEXA).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Beta-hexosaminidase subunit alpha (HEXA).	[8]

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] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 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.
• [6] A role for the autophagy regulator Transcription Factor EB in amiodarone-induced phospholipidosis. Biochem Pharmacol. 2015 Jun 1;95(3):201-9. doi: 10.1016/j.bcp.2015.03.017. Epub 2015 Apr 13.
• [7] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [8] 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.
• [9] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [10] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [11] 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.