Details of Drug Off-Target (DOT)

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

• DOT Name: Glutamine synthetase (GLUL)
• Synonyms: GS; EC 6.3.1.2; Glutamate--ammonia ligase; Palmitoyltransferase GLUL; EC 2.3.1.225
• Gene Name: GLUL
• Related Disease: Congenital brain dysgenesis due to glutamine synthetase deficiency
• UniProt ID: GLNA_HUMAN
• PDB ID: 2OJW; 2QC8; 7EVT; 8DNU
• EC Number: 2.3.1.225; 6.3.1.2
• Pfam ID: PF00120 ; PF03951
• Sequence:
  MTTSASSHLNKGIKQVYMSLPQGEKVQAMYIWIDGTGEGLRCKTRTLDSEPKCVEELPEW
  NFDGSSTLQSEGSNSDMYLVPAAMFRDPFRKDPNKLVLCEVFKYNRRPAETNLRHTCKRI
  MDMVSNQHPWFGMEQEYTLMGTDGHPFGWPSNGFPGPQGPYYCGVGADRAYGRDIVEAHY
  RACLYAGVKIAGTNAEVMPAQWEFQIGPCEGISMGDHLWVARFILHRVCEDFGVIATFDP
  KPIPGNWNGAGCHTNFSTKAMREENGLKYIEEAIEKLSKRHQYHIRAYDPKGGLDNARRL
  TGFHETSNINDFSAGVANRSASIRIPRTVGQEKKGYFEDRRPSANCDPFSVTEALIRTCL
  LNETGDEPFQYKN
• Function: Glutamine synthetase that catalyzes the ATP-dependent conversion of glutamate and ammonia to glutamine. Its role depends on tissue localization: in the brain, it regulates the levels of toxic ammonia and converts neurotoxic glutamate to harmless glutamine, whereas in the liver, it is one of the enzymes responsible for the removal of ammonia. Essential for proliferation of fetal skin fibroblasts. Independently of its glutamine synthetase activity, required for endothelial cell migration during vascular development: acts by regulating membrane localization and activation of the GTPase RHOJ, possibly by promoting RHOJ palmitoylation. May act as a palmitoyltransferase for RHOJ: able to autopalmitoylate and then transfer the palmitoyl group to RHOJ. Plays a role in ribosomal 40S subunit biogenesis.
• Tissue Specificity: Expressed in endothelial cells.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Nitrogen metabolism (hsa00910)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
  Necroptosis (hsa04217)
  Glutamatergic sy.pse (hsa04724)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  Glutamate and glutamine metabolism (R-HSA-8964539)
  Astrocytic Glutamate-Glutamine Uptake And Metabolism (R-HSA-210455)
• BioCyc Pathway: MetaCyc:HS06066-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital brain dysgenesis due to glutamine synthetase deficiency	DISVG47Q	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Glutamine synthetase (GLUL) affects the response to substance of Mitoxantrone.	[29]

29 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 Glutamine synthetase (GLUL).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamine synthetase (GLUL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutamine synthetase (GLUL).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutamine synthetase (GLUL).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutamine synthetase (GLUL).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutamine synthetase (GLUL).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutamine synthetase (GLUL).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutamine synthetase (GLUL).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Glutamine synthetase (GLUL).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glutamine synthetase (GLUL).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Glutamine synthetase (GLUL).	[4]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Glutamine synthetase (GLUL).	[12]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Glutamine synthetase (GLUL).	[13]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Glutamine synthetase (GLUL).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Glutamine synthetase (GLUL).	[15]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Glutamine synthetase (GLUL).	[4]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of Glutamine synthetase (GLUL).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glutamine synthetase (GLUL).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glutamine synthetase (GLUL).	[18]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the expression of Glutamine synthetase (GLUL).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Glutamine synthetase (GLUL).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glutamine synthetase (GLUL).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glutamine synthetase (GLUL).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamine synthetase (GLUL).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Glutamine synthetase (GLUL).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Glutamine synthetase (GLUL).	[26]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Glutamine synthetase (GLUL).	[27]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Glutamine synthetase (GLUL).	[28]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Glutamine synthetase (GLUL).	[4]

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 decreases the methylation of Glutamine synthetase (GLUL).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Glutamine synthetase (GLUL).	[23]

References

• [1] Natural course of glutamine synthetase deficiency in a 3 year old patient. Mol Genet Metab. 2011 May;103(1):89-91. doi: 10.1016/j.ymgme.2011.02.001. Epub 2011 Feb 4.
• [2] 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.
• [3] 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.
• [4] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [5] 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.
• [6] 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.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [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] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [13] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [14] Anti-inflammatory agent indomethacin reduces invasion and alters metabolism in a human breast cancer cell line. Neoplasia. 2007 Mar;9(3):222-35.
• [15] 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.
• [16] Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] 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.
• [24] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [25] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [27] Effects of PQ's cytotoxicity on secretory vesicles in astroglia: Expression alternation of secretogranin II and its potential interaction with intracellular factors. Biochem Biophys Res Commun. 2018 Mar 4;497(2):675-682. doi: 10.1016/j.bbrc.2018.02.130. Epub 2018 Feb 16.
• [28] 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.
• [29] 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.