Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPRSHX5)

• DOT Name: D-glucuronyl C5-epimerase (GLCE)
• Synonyms: EC 5.1.3.17; Heparan sulfate C5-epimerase; Hsepi; Heparin/heparan sulfate:glucuronic acid C5-epimerase; Heparosan-N-sulfate-glucuronate 5-epimerase
• Gene Name: GLCE
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Advanced cancer
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Prostate disease
  Small-cell lung cancer
  Triple negative breast cancer
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
• UniProt ID: GLCE_HUMAN
• PDB ID: 6HZZ; 6I01; 6I02
• EC Number: 5.1.3.17
• Pfam ID: PF06662 ; PF21174
• Sequence:
  MRCLAARVNYKTLIIICALFTLVTVLLWNKCSSDKAIQFPRRSSSGFRVDGFEKRAAASE
  SNNYMNHVAKQQSEEAFPQEQQKAPPVVGGFNSNVGSKVLGLKYEEIDCLINDEHTIKGR
  REGNEVFLPFTWVEKYFDVYGKVVQYDGYDRFEFSHSYSKVYAQRAPYHPDGVFMSFEGY
  NVEVRDRVKCISGVEGVPLSTQWGPQGYFYPIQIAQYGLSHYSKNLTEKPPHIEVYETAE
  DRDKNKPNDWTVPKGCFMANVADKSRFTNVKQFIAPETSEGVSLQLGNTKDFIISFDLKF
  LTNGSVSVVLETTEKNQLFTIHYVSNAQLIAFKERDIYYGIGPRTSWSTVTRDLVTDLRK
  GVGLSNTKAVKPTKIMPKKVVRLIAKGKGFLDNITISTTAHMAAFFAASDWLVRNQDEKG
  GWPIMVTRKLGEGFKSLEPGWYSAMAQGQAISTLVRAYLLTKDHIFLNSALRATAPYKFL
  SEQHGVKAVFMNKHDWYEEYPTTPSSFVLNGFMYSLIGLYDLKETAGEKLGKEARSLYER
  GMESLKAMLPLYDTGSGTIYDLRHFMLGIAPNLARWDYHTTHINQLQLLSTIDESPVFKE
  FVKRWKSYLKGSRAKHN
• Function: Converts D-glucuronic acid residues adjacent to N-sulfate sugar residues to L-iduronic acid residues, both in maturing heparan sulfate (HS) and heparin chains. This is important for further modifications that determine the specificity of interactions between these glycosaminoglycans and proteins.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Prostate neoplasm	DISHDKGQ	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Prostate disease	DISFVG19	Strong	Altered Expression	[2]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[4]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[5]
Frontotemporal dementia	DISKYHXL	Disputed	Biomarker	[5]

21 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 D-glucuronyl C5-epimerase (GLCE).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of D-glucuronyl C5-epimerase (GLCE).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of D-glucuronyl C5-epimerase (GLCE).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of D-glucuronyl C5-epimerase (GLCE).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of D-glucuronyl C5-epimerase (GLCE).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of D-glucuronyl C5-epimerase (GLCE).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of D-glucuronyl C5-epimerase (GLCE).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of D-glucuronyl C5-epimerase (GLCE).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of D-glucuronyl C5-epimerase (GLCE).	[25]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of D-glucuronyl C5-epimerase (GLCE).	[26]

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 increases the methylation of D-glucuronyl C5-epimerase (GLCE).	[20]

References

• [1] D-glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells.Tumour Biol. 2014 Apr;35(4):3237-45. doi: 10.1007/s13277-013-1423-6. Epub 2013 Nov 22.
• [2] Heterogeneity of d-glucuronyl C5-epimerase expression and epigenetic regulation in prostate cancer.Cancer Med. 2013 Oct;2(5):654-61. doi: 10.1002/cam4.108. Epub 2013 Aug 5.
• [3] GLCE rs3865014 (Val597Ile) polymorphism is associated with breast cancer susceptibility and triple-negative breast cancer in Siberian population.Gene. 2017 Sep 10;628:224-229. doi: 10.1016/j.gene.2017.07.054. Epub 2017 Jul 20.
• [4] D-glucuronyl C5-epimerase suppresses small-cell lung cancer cell proliferation in vitro and tumour growth in vivo.Br J Cancer. 2011 Jun 28;105(1):74-82. doi: 10.1038/bjc.2011.170. Epub 2011 Jun 7.
• [5] Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy.PLoS Genet. 2019 Dec 13;15(12):e1008526. doi: 10.1371/journal.pgen.1008526. eCollection 2019 Dec.
• [6] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [7] 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.
• [8] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [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] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
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• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.