Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL71J7T)

• DOT Name: Gamma-glutamyl hydrolase (GGH)
• Synonyms: EC 3.4.19.9; Conjugase; GH; Gamma-Glu-X carboxypeptidase
• Gene Name: GGH
• UniProt ID: GGH_HUMAN
• PDB ID: 1L9X
• EC Number: 3.4.19.9
• Pfam ID: PF07722
• Sequence:
  MASPGCLLCVLGLLLCGAASLELSRPHGDTAKKPIIGILMQKCRNKVMKNYGRYYIAASY
  VKYLESAGARVVPVRLDLTEKDYEILFKSINGILFPGGSVDLRRSDYAKVAKIFYNLSIQ
  SFDDGDYFPVWGTCLGFEELSLLISGECLLTATDTVDVAMPLNFTGGQLHSRMFQNFPTE
  LLLSLAVEPLTANFHKWSLSVKNFTMNEKLKKFFNVLTTNTDGKIEFISTMEGYKYPVYG
  VQWHPEKAPYEWKNLDGISHAPNAVKTAFYLAEFFVNEARKNNHHFKSESEEEKALIYQF
  SPIYTGNISSFQQCYIFD
• Function: Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Biosynthesis of cofactors (hsa01240)
  Antifolate resistance (hsa01523)
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Pemetrexed	DMMX2E6	Approved	Gamma-glutamyl hydrolase (GGH) affects the response to substance of Pemetrexed.	[21]

22 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 Gamma-glutamyl hydrolase (GGH).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gamma-glutamyl hydrolase (GGH).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gamma-glutamyl hydrolase (GGH).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gamma-glutamyl hydrolase (GGH).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-glutamyl hydrolase (GGH).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gamma-glutamyl hydrolase (GGH).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Gamma-glutamyl hydrolase (GGH).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Gamma-glutamyl hydrolase (GGH).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Gamma-glutamyl hydrolase (GGH).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Gamma-glutamyl hydrolase (GGH).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gamma-glutamyl hydrolase (GGH).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Gamma-glutamyl hydrolase (GGH).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Gamma-glutamyl hydrolase (GGH).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Gamma-glutamyl hydrolase (GGH).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Gamma-glutamyl hydrolase (GGH).	[14]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Gamma-glutamyl hydrolase (GGH).	[15]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Gamma-glutamyl hydrolase (GGH).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Gamma-glutamyl hydrolase (GGH).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gamma-glutamyl hydrolase (GGH).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Gamma-glutamyl hydrolase (GGH).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Gamma-glutamyl hydrolase (GGH).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Gamma-glutamyl hydrolase (GGH).	[20]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [7] 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.
• [8] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis. Arthritis Rheum. 2013 Nov;65(11):2791-802.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] The reduced folate carrier (RFC) is cytotoxic to cells under conditions of severe folate deprivationRFC as a double edged sword in folate homeostasis. J Biol Chem. 2008 Jul 25;283(30):20687-95.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [17] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [18] 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.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.