Details of Drug Off-Target (DOT)

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

• DOT Name: Hexosaminidase D (HEXD)
• Synonyms: EC 3.2.1.52; Beta-N-acetylhexosaminidase; Beta-hexosaminidase D; Hexosaminidase domain-containing protein; N-acetyl-beta-galactosaminidase
• Gene Name: HEXD
• Related Disease:
  GM2 gangliosidosis
  Sandhoff disease
  Tay-sachs disease
  Timothy syndrome
  Tourette syndrome
  Tuberous sclerosis
• UniProt ID: HEXD_HUMAN
• EC Number: 3.2.1.52
• Pfam ID: PF00728
• Sequence:
  MSGSTPFQMRLVHLDLKGAPPKVSYLSEIFPLFRALGANGLLIEYEDMFPYEGPLRLLRA
  KYAYSPSEIKEILHLAGLNELEVIPLVQTFGHMEFVLKHTAFAHLREVGSFPCTLNPHEA
  ESLALVGAMIDQVLELHPGAQRLHIGCDEVYYLGEGEASRRWLQQEQNSTGKLCLSHMRA
  VASGVKARRPSVTPLVWDDMLRDLPEDQLAASGVPQLVEPVLWDYTADLDVHGKVLLMQK
  YRRCGFPQLWAASAFKGATGPSQAVPPVEHHLRNHVQWLQVAGSGPTDSLQGIILTGWQR
  YDHYSVLCELLPAGVPSLAACLQLLLRGGFDEDVKAKVENLLGISSLEKTDPVREGAGSF
  PGSNILALVTQVSLHLRSSVDALLEGNRYVTGWFSPYHRQRKLIHPVMVQHIQPAALSLL
  AQWSTLVQELEAALQLAFYPDAVEEWLEENVHPSLQRLQALLQDLSEVSAPPLPPTSPGR
  DVAQDP
• Function: Has hexosaminidase activity. Responsible for the cleavage of the monosaccharides N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) from cellular substrates. Has a preference for galactosaminide over glucosaminide substrates.
• Tissue Specificity: Expressed in synovial fibroblasts and synovial membranes.
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
GM2 gangliosidosis	DISPT716	Definitive	Genetic Variation	[1]
Sandhoff disease	DISELKA4	Strong	Genetic Variation	[2]
Tay-sachs disease	DISWG5B4	moderate	Altered Expression	[3]
Timothy syndrome	DISBXBZP	Limited	Biomarker	[4]
Tourette syndrome	DISX9D54	Limited	Biomarker	[4]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[4]

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 Hexosaminidase D (HEXD).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Hexosaminidase D (HEXD).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hexosaminidase D (HEXD).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hexosaminidase D (HEXD).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hexosaminidase D (HEXD).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Hexosaminidase D (HEXD).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Hexosaminidase D (HEXD).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Hexosaminidase D (HEXD).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Hexosaminidase D (HEXD).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Hexosaminidase D (HEXD).	[13]

References

• [1] Reversibility of neuropathology in Tay-Sachs-related diseases.Hum Mol Genet. 2014 Feb 1;23(3):730-48. doi: 10.1093/hmg/ddt459. Epub 2013 Sep 20.
• [2] Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.Mol Genet Metab. 2015 Sep-Oct;116(1-2):80-7. doi: 10.1016/j.ymgme.2015.05.003. Epub 2015 May 8.
• [3] Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group.Proc Natl Acad Sci U S A. 1988 Jun;85(11):3955-9. doi: 10.1073/pnas.85.11.3955.
• [4] Absence of metabolic cross-correction in Tay-Sachs cells: implications for gene therapy.J Biol Chem. 2002 Jun 7;277(23):20177-84. doi: 10.1074/jbc.M106164200. Epub 2002 Mar 28.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [13] 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.
• [14] 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.