Details of Drug Off-Target (DOT)

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

• DOT Name: Glutathione synthetase (GSS)
• Synonyms: GSH synthetase; GSH-S; EC 6.3.2.3; Glutathione synthase
• Gene Name: GSS
• Related Disease:
  Inherited glutathione synthetase deficiency
  Glutathione synthetase deficiency with 5-oxoprolinuria
• UniProt ID: GSHB_HUMAN
• PDB ID: 2HGS
• EC Number: 6.3.2.3
• Pfam ID: PF03917 ; PF03199
• Sequence:
  MATNWGSLLQDKQQLEELARQAVDRALAEGVLLRTSQEPTSSEVVSYAPFTLFPSLVPSA
  LLEQAYAVQMDFNLLVDAVSQNAAFLEQTLSSTIKQDDFTARLFDIHKQVLKEGIAQTVF
  LGLNRSDYMFQRSADGSPALKQIEINTISASFGGLASRTPAVHRHVLSVLSKTKEAGKIL
  SNNPSKGLALGIAKAWELYGSPNALVLLIAQEKERNIFDQRAIENELLARNIHVIRRTFE
  DISEKGSLDQDRRLFVDGQEIAVVYFRDGYMPRQYSLQNWEARLLLERSHAAKCPDIATQ
  LAGTKKVQQELSRPGMLEMLLPGQPEAVARLRATFAGLYSLDVGEEGDQAIAEALAAPSR
  FVLKPQREGGGNNLYGEEMVQALKQLKDSEERASYILMEKIEPEPFENCLLRPGSPARVV
  QCISELGIFGVYVRQEKTLVMNKHVGHLLRTKAIEHADGGVAAGVAVLDNPYPV
• Function: Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner. Glutathione (gamma-glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol in living aerobic cells and is required for numerous processes including the protection of cells against oxidative damage, amino acid transport, the detoxification of foreign compounds, the maintenance of protein sulfhydryl groups in a reduced state and acts as a cofactor for a number of enzymes. Participates in ophthalmate biosynthesis in hepatocytes.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Ferroptosis (hsa04216)
• Reactome Pathway:
  Defective GSS causes GSS deficiency (R-HSA-5579006)
  Glutathione synthesis and recycling (R-HSA-174403)
• BioCyc Pathway: MetaCyc:HS02174-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited glutathione synthetase deficiency	DISVQEGM	Definitive	Autosomal recessive	[1]
Glutathione synthetase deficiency with 5-oxoprolinuria	DISCUWVE	Strong	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Misonidazole	DMYB0HK	Investigative	Glutathione synthetase (GSS) increases the response to substance of Misonidazole.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Glutathione synthetase (GSS).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutathione synthetase (GSS).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutathione synthetase (GSS).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutathione synthetase (GSS).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutathione synthetase (GSS).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutathione synthetase (GSS).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Glutathione synthetase (GSS).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Glutathione synthetase (GSS).	[10]
Triclosan	DMZUR4N	Approved	Triclosan affects the expression of Glutathione synthetase (GSS).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Glutathione synthetase (GSS).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Glutathione synthetase (GSS).	[13]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Glutathione synthetase (GSS).	[14]
Mercaptopurine	DMTM2IK	Approved	Mercaptopurine increases the expression of Glutathione synthetase (GSS).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Glutathione synthetase (GSS).	[15]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Glutathione synthetase (GSS).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Glutathione synthetase (GSS).	[7]
CERC-801	DM3SZ7P	Phase 2	CERC-801 decreases the expression of Glutathione synthetase (GSS).	[17]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Glutathione synthetase (GSS).	[14]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Glutathione synthetase (GSS).	[19]
PMID26560530-Compound-25	DMZ43OM	Patented	PMID26560530-Compound-25 increases the activity of Glutathione synthetase (GSS).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glutathione synthetase (GSS).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutathione synthetase (GSS).	[22]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Glutathione synthetase (GSS).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Glutathione synthetase (GSS).	[24]
Paraoxon	DMN4ZKC	Investigative	Paraoxon increases the expression of Glutathione synthetase (GSS).	[25]
	DM9CEI5		affects the expression of Glutathione synthetase (GSS).	[26]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the expression of Glutathione synthetase (GSS).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Glutathione synthetase (GSS).	[18]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione?. J Inherit Metab Dis. 2002 Nov;25(7):577-84. doi: 10.1023/a:1022095324407.
• [3] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Interplay between cellular methyl metabolism and adaptive efflux during oncogenic transformation from chronic arsenic exposure in human cells. J Biol Chem. 2008 Jul 11;283(28):19342-50.
• [10] Chromium III histidinate exposure modulates gene expression in HaCaT human keratinocytes exposed to oxidative stress. Biol Trace Elem Res. 2010 Oct;137(1):23-39.
• [11] The modulatory effect of triclosan on the reversion of the activated phenotype of LX-2 hepatic stellate cells. J Biochem Mol Toxicol. 2020 Jan;34(1):e22413. doi: 10.1002/jbt.22413. Epub 2019 Nov 12.
• [12] Essential role of Nrf2 in protection against hydroquinone- and benzoquinone-induced cytotoxicity. Toxicol In Vitro. 2011 Mar;25(2):521-9.
• [13] Petit E, Langouet S, Akhdar H, Nicolas-Nicolaz C, Guillouzo A, Morel F. Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes. Toxicol In Vitro. 2008;22(3):632-642. [PMID: 18222062]
• [14] Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells. Biochem Pharmacol. 2009 Mar 1;77(5):858-66. doi: 10.1016/j.bcp.2008.11.012. Epub 2008 Nov 25.
• [15] Resveratrol protects against deoxynivalenol-induced ferroptosis in HepG2 cells. Toxicology. 2023 Aug 1;494:153589. doi: 10.1016/j.tox.2023.153589. Epub 2023 Jul 5.
• [16] Impact of epigallocatechin gallate on gene expression profiles of human hepatocellular carcinoma cell lines BEL7404/ADM and BEL7402/5-FU. Ai Zheng. 2008 Oct;27(10):1056-64.
• [17] Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress. Neurochem Int. 2013 Apr;62(5):603-9.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [20] Anethole dithiolethione regulates oxidant-induced tyrosine kinase activation in endothelial cells. Antioxid Redox Signal. 2000 Winter;2(4):789-99. doi: 10.1089/ars.2000.2.4-789.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [24] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [25] Oxidative stress resulting from exposure of a human salivary gland cells to paraoxon: an in vitro model for organophosphate oral exposure. Toxicol In Vitro. 2014 Aug;28(5):715-21. doi: 10.1016/j.tiv.2014.01.009. Epub 2014 Jan 29.
• [26] Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of glutathione synthetic enzymes and contributes to cholestatic liver injury in mice. Hepatology. 2010 Apr;51(4):1291-301. doi: 10.1002/hep.23471.
• [27] Radiosensitizing and cytotoxic properties of misonidazole on glutathione synthetase deficient human fibroblasts. Int J Radiat Biol Relat Stud Phys Chem Med. 1985 Aug;48(2):213-21. doi: 10.1080/09553008514551211.