Details of Drug Off-Target (DOT)

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

• DOT Name: Beta-hexosaminidase subunit beta (HEXB)
• Synonyms: EC 3.2.1.52; Beta-N-acetylhexosaminidase subunit beta; Hexosaminidase subunit B; Cervical cancer proto-oncogene 7 protein; HCC-7; N-acetyl-beta-glucosaminidase subunit beta
• Gene Name: HEXB
• Related Disease: Sandhoff disease
• UniProt ID: HEXB_HUMAN
• PDB ID: 1NOU; 1NOW; 1NP0; 1O7A; 2GJX; 2GK1; 3LMY; 5BRO
• EC Number: 3.2.1.52
• Pfam ID: PF00728 ; PF14845
• Sequence:
  MELCGLGLPRPPMLLALLLATLLAAMLALLTQVALVVQVAEAARAPSVSAKPGPALWPLP
  LLVKMTPNLLHLAPENFYISHSPNSTAGPSCTLLEEAFRRYHGYIFGFYKWHHEPAEFQA
  KTQVQQLLVSITLQSECDAFPNISSDESYTLLVKEPVAVLKANRVWGALRGLETFSQLVY
  QDSYGTFTINESTIIDSPRFSHRGILIDTSRHYLPVKIILKTLDAMAFNKFNVLHWHIVD
  DQSFPYQSITFPELSNKGSYSLSHVYTPNDVRMVIEYARLRGIRVLPEFDTPGHTLSWGK
  GQKDLLTPCYSRQNKLDSFGPINPTLNTTYSFLTTFFKEISEVFPDQFIHLGGDEVEFKC
  WESNPKIQDFMRQKGFGTDFKKLESFYIQKVLDIIATINKGSIVWQEVFDDKAKLAPGTI
  VEVWKDSAYPEELSRVTASGFPVILSAPWYLDLISYGQDWRKYYKVEPLDFGGTQKQKQL
  FIGGEACLWGEYVDATNLTPRLWPRASAVGERLWSSKDVRDMDDAYDRLTRHRCRMVERG
  IAAQPLYAGYCNHENM
• 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 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. During fertilization is responsible, at least in part, for the zona block to polyspermy. Present in the cortical granules of non-activated oocytes, is exocytosed during the cortical reaction in response to oocyte activation and inactivates the sperm galactosyltransferase-binding site, accounting for the block in sperm binding to the zona pellucida.
• 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 HEXB causes GM2G2 (R-HSA-3656248)
  Neutrophil degranulation (R-HSA-6798695)
  Glycosphingolipid catabolism (R-HSA-9840310)
  Keratan sulfate degradation (R-HSA-2022857)
• BioCyc Pathway: MetaCyc:HS00629-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
Sandhoff disease	DISELKA4	Definitive	Autosomal recessive	[1]

16 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 Beta-hexosaminidase subunit beta (HEXB).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-hexosaminidase subunit beta (HEXB).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Beta-hexosaminidase subunit beta (HEXB).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Beta-hexosaminidase subunit beta (HEXB).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Beta-hexosaminidase subunit beta (HEXB).	[10]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Beta-hexosaminidase subunit beta (HEXB).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Beta-hexosaminidase subunit beta (HEXB).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[20]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Beta-hexosaminidase subunit beta (HEXB).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pyrimethamine	DM5X7VY	Approved	Pyrimethamine affects the binding of Beta-hexosaminidase subunit beta (HEXB).	[12]
Dextromethorphan	DMUDJZM	Approved	Dextromethorphan increases the secretion of Beta-hexosaminidase subunit beta (HEXB).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the secretion of Beta-hexosaminidase subunit beta (HEXB).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Beta-hexosaminidase subunit beta (HEXB).	[18]

References

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• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
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• [9] 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.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
• [12] Crystal structure of -hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. J Med Chem. 2011 Mar 10;54(5):1421-9. doi: 10.1021/jm101443u. Epub 2011 Jan 25.
• [13] Dextromethorphan - A widely-used cough suppressant - Induces local anaphylaxis via MRGPRX2 on mast cells. Chem Biol Interact. 2020 Oct 1;330:109248. doi: 10.1016/j.cbi.2020.109248. Epub 2020 Aug 29.
• [14] 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.
• [15] Gnetin H isolated from Paeonia anomala inhibits FcRI-mediated mast cell signaling and degranulation. J Ethnopharmacol. 2014 Jul 3;154(3):798-806.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.
• [21] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.