Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWV79YD)

• DOT Name: GDP-mannose 4,6 dehydratase (GMDS)
• Synonyms: EC 4.2.1.47; GDP-D-mannose dehydratase; GMD
• Gene Name: GMDS
• UniProt ID: GMDS_HUMAN
• PDB ID: 1T2A; 5IN4; 5IN5; 6GPJ; 6GPK; 6GPL; 6Q94
• EC Number: 4.2.1.47
• Pfam ID: PF16363
• Sequence:
  MAHAPARCPSARGSGDGEMGKPRNVALITGITGQDGSYLAEFLLEKGYEVHGIVRRSSSF
  NTGRIEHLYKNPQAHIEGNMKLHYGDLTDSTCLVKIINEVKPTEIYNLGAQSHVKISFDL
  AEYTADVDGVGTLRLLDAVKTCGLINSVKFYQASTSELYGKVQEIPQKETTPFYPRSPYG
  AAKLYAYWIVVNFREAYNLFAVNGILFNHESPRRGANFVTRKISRSVAKIYLGQLECFSL
  GNLDAKRDWGHAKDYVEAMWLMLQNDEPEDFVIATGEVHSVREFVEKSFLHIGKTIVWEG
  KNENEVGRCKETGKVHVTVDLKYYRPTEVDFLQGDCTKAKQKLNWKPRVAFDELVREMVH
  ADVELMRTNPNA
• Function: Catalyzes the conversion of GDP-D-mannose to GDP-4-dehydro-6-deoxy-D-mannose.
• Tissue Specificity: Highly expressed in pancreas and small intestine. Expressed in thymus, protstate, colon, heart, placenta, liver and kidney. Expressed at low levels in spleen, testis, brain and lung.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Amino sugar and nucleotide sugar metabolism (hsa00520)
  Metabolic pathways (hsa01100)
  Biosynthesis of nucleotide sugars (hsa01250)
• Reactome Pathway: GDP-fucose biosynthesis (R-HSA-6787639)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	GDP-mannose 4,6 dehydratase (GMDS) affects the response to substance of Topotecan.	[16]
Dopamine	DMPGUCF	Approved	GDP-mannose 4,6 dehydratase (GMDS) increases the Intervertebral disc protrusion ADR of Dopamine.	[17]

12 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 GDP-mannose 4,6 dehydratase (GMDS).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[9]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of GDP-mannose 4,6 dehydratase (GMDS).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of GDP-mannose 4,6 dehydratase (GMDS).	[14]

2 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 GDP-mannose 4,6 dehydratase (GMDS).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of GDP-mannose 4,6 dehydratase (GMDS).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanosine-5'-Diphosphate	DM0MUKQ	Investigative	Guanosine-5'-Diphosphate affects the binding of GDP-mannose 4,6 dehydratase (GMDS).	[15]
Guanosine-5'-Monophosphate	DM3SLZK	Investigative	Guanosine-5'-Monophosphate affects the binding of GDP-mannose 4,6 dehydratase (GMDS).	[15]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [10] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [11] Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens. Arch Toxicol. 2019 Nov;93(11):3335-3344. doi: 10.1007/s00204-019-02569-5. Epub 2019 Sep 25.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [15] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [16] 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.
• [17] Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search. Mol Psychiatry. 2011 Sep;16(9):927-37, 881. doi: 10.1038/mp.2011.32. Epub 2011 Apr 19.