Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ108VJ)

• DOT Name: Dermatan-sulfate epimerase (DSE)
• Synonyms: DS epimerase; EC 5.1.3.19; Chondroitin-glucuronate 5-epimerase; Squamous cell carcinoma antigen recognized by T-cells 2; SART-2
• Gene Name: DSE
• Related Disease:
  Advanced cancer
  Cardiovascular disease
  Ehlers-Danlos syndrome
  Ehlers-Danlos syndrome, musculocontractural type 2
  Hepatocellular carcinoma
  Neoplasm
  Type-1/2 diabetes
  Ehlers-Danlos syndrome, musculocontractural type
  Breast cancer
  Breast carcinoma
• UniProt ID: DSE_HUMAN
• PDB ID: 6HZN
• EC Number: 5.1.3.19
• Pfam ID: PF16332
• Sequence:
  MRTHTRGAPSVFFIYLLCFVSAYITDENPEVMIPFTNANYDSHPMLYFSRAEVAELQLRA
  ASSHEHIAARLTEAVHTMLSSPLEYLPPWDPKDYSARWNEIFGNNLGALAMFCVLYPENI
  EARDMAKDYMERMAAQPSWLVKDAPWDEVPLAHSLVGFATAYDFLYNYLSKTQQEKFLEV
  IANASGYMYETSYRRGWGFQYLHNHQPTNCMALLTGSLVLMNQGYLQEAYLWTKQVLTIM
  EKSLVLLREVTDGSLYEGVAYGSYTTRSLFQYMFLVQRHFNINHFGHPWLKQHFAFMYRT
  ILPGFQRTVAIADSNYNWFYGPESQLVFLDKFVMRNGSGNWLADQIRRNRVVEGPGTPSK
  GQRWCTLHTEFLWYDGSLKSVPPPDFGTPTLHYFEDWGVVTYGSALPAEINRSFLSFKSG
  KLGGRAIYDIVHRNKYKDWIKGWRNFNAGHEHPDQNSFTFAPNGVPFITEALYGPKYTFF
  NNVLMFSPAVSKSCFSPWVGQVTEDCSSKWSKYKHDLAASCQGRVVAAEEKNGVVFIRGE
  GVGAYNPQLNLKNVQRNLILLHPQLLLLVDQIHLGEESPLETAASFFHNVDVPFEETVVD
  GVHGAFIRQRDGLYKMYWMDDTGYSEKATFASVTYPRGYPYNGTNYVNVTMHLRSPITRA
  AYLFIGPSIDVQSFTVHGDSQQLDVFIATSKHAYATYLWTGEATGQSAFAQVIADRHKIL
  FDRNSAIKSSIVPEVKDYAAIVEQNLQHFKPVFQLLEKQILSRVRNTASFRKTAERLLRF
  SDKRQTEEAIDRIFAISQQQQQQSKSKKNRRAGKRYKFVDAVPDIFAQIEVNEKKIRQKA
  QILAQKELPIDEDEEMKDLLDFADVTYEKHKNGGLIKGRFGQARMVTTTHSRAPSLSASY
  TRLFLILNIAIFFVMLAMQLTYFQRAQSLHGQRCLYAVLLIDSCILLWLYSSCSQSQC
• Function: Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues. Plays an important role in the biosynthesis of the glycosaminoglycan/mucopolysaccharide dermatan sulfate.
• Tissue Specificity: Ubiquitously expressed with higher expression in kidney and ovary and lower expression in brain, colon and thymus. Also expressed in renal cell carcinomas, brain tumors, and in a part of melanomas and adenocarcinomas from organs other than the breast. Expressed in squamous cell carcinomas (SCC), glioma, and some adenocarcinoma cell lines, but not in breast cancer cell lines or any normal tissues (at protein level).
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Dermatan sulfate biosynthesis (R-HSA-2022923)
• BioCyc Pathway: MetaCyc:HS03472-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[2]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Genetic Variation	[3]
Ehlers-Danlos syndrome, musculocontractural type 2	DISVRWVW	Strong	Autosomal recessive	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]
Ehlers-Danlos syndrome, musculocontractural type	DIS6XBQP	Supportive	Autosomal recessive	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[6]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Dermatan-sulfate epimerase (DSE) affects the response to substance of Mitomycin.	[20]
Topotecan	DMP6G8T	Approved	Dermatan-sulfate epimerase (DSE) affects the response to substance of Topotecan.	[20]
Capecitabine	DMTS85L	Approved	Dermatan-sulfate epimerase (DSE) decreases the response to substance of Capecitabine.	[21]

15 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 Dermatan-sulfate epimerase (DSE).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dermatan-sulfate epimerase (DSE).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dermatan-sulfate epimerase (DSE).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dermatan-sulfate epimerase (DSE).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dermatan-sulfate epimerase (DSE).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Dermatan-sulfate epimerase (DSE).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dermatan-sulfate epimerase (DSE).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dermatan-sulfate epimerase (DSE).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dermatan-sulfate epimerase (DSE).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Dermatan-sulfate epimerase (DSE).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dermatan-sulfate epimerase (DSE).	[17]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Dermatan-sulfate epimerase (DSE).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dermatan-sulfate epimerase (DSE).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dermatan-sulfate epimerase (DSE).	[19]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Dermatan-sulfate epimerase (DSE).	[13]

References

• [1] DSE regulates the malignant characters of hepatocellular carcinoma cells by modulating CCL5/CCR1 axis.Am J Cancer Res. 2019 Feb 1;9(2):347-362. eCollection 2019.
• [2] Effects of visceral adipose tissue reduction on CVD risk factors independent of weight loss: The Look AHEAD study.Endocr Res. 2017 May;42(2):86-95. doi: 10.1080/07435800.2016.1194856. Epub 2016 Jun 28.
• [3] DSE associated musculocontractural EDS, a milder phenotype or phenotypic variability.Eur J Med Genet. 2020 Apr;63(4):103798. doi: 10.1016/j.ejmg.2019.103798. Epub 2019 Oct 23.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome. Hum Mol Genet. 2013 Sep 15;22(18):3761-72. doi: 10.1093/hmg/ddt227. Epub 2013 May 23.
• [6] Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients' Outcome.Curr Cancer Drug Targets. 2019;19(3):210-221. doi: 10.2174/1568009618666180706165845.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] 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.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] 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.
• [21] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.