Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYDA1Z7)

• DOT Name: Glutathione hydrolase 1 proenzyme (GGT1)
• Synonyms: EC 3.4.19.13; Gamma-glutamyltransferase 1; Gamma-glutamyltranspeptidase 1; GGT 1; EC 2.3.2.2; Leukotriene-C4 hydrolase; EC 3.4.19.14; CD antigen CD224
• Gene Name: GGT1
• Related Disease: Gamma-glutamyl transpeptidase deficiency
• UniProt ID: GGT1_HUMAN
• PDB ID: 4GDX; 4GG2; 4Z9O; 4ZBK; 4ZC6; 4ZCG; 5V4Q
• EC Number: 2.3.2.2; 3.4.19.13; 3.4.19.14
• Pfam ID: PF01019
• Sequence:
  MKKKLVVLGLLAVVLVLVIVGLCLWLPSASKEPDNHVYTRAAVAADAKQCSKIGRDALRD
  GGSAVDAAIAALLCVGLMNAHSMGIGGGLFLTIYNSTTRKAEVINAREVAPRLAFATMFN
  SSEQSQKGGLSVAVPGEIRGYELAHQRHGRLPWARLFQPSIQLARQGFPVGKGLAAALEN
  KRTVIEQQPVLCEVFCRDRKVLREGERLTLPQLADTYETLAIEGAQAFYNGSLTAQIVKD
  IQAAGGIVTAEDLNNYRAELIEHPLNISLGDVVLYMPSAPLSGPVLALILNILKGYNFSR
  ESVESPEQKGLTYHRIVEAFRFAYAKRTLLGDPKFVDVTEVVRNMTSEFFAAQLRAQISD
  DTTHPISYYKPEFYTPDDGGTAHLSVVAEDGSAVSATSTINLYFGSKVRSPVSGILFNNE
  MDDFSSPSITNEFGVPPSPANFIQPGKQPLSSMCPTIMVGQDGQVRMVVGAAGGTQITTA
  TALAIIYNLWFGYDVKRAVEEPRLHNQLLPNVTTVERNIDQAVTAALETRHHHTQIASTF
  IAVVQAIVRTAGGWAAASDSRKGGEPAGY
• Function: Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate, MCTR1) and other gamma-glutamyl compounds (such as leukotriene C4, LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound. Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4; [Isoform 3]: Seems to be inactive.
• Tissue Specificity: Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.; [Isoform 3]: Lung-specific.
• KEGG Pathway:
  Taurine and hypotaurine metabolism (hsa00430)
  Glutathione metabolism (hsa00480)
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Aflatoxin activation and detoxification (R-HSA-5423646)
  Defective GGT1 causes GLUTH (R-HSA-5579022)
  Defective GGT1 in aflatoxin detoxification causes GLUTH (R-HSA-9035968)
  LTC4-CYSLTR mediated IL4 production (R-HSA-9664535)
  Paracetamol ADME (R-HSA-9753281)
  Glutathione synthesis and recycling (R-HSA-174403)
• BioCyc Pathway: MetaCyc:MONOMER66-34394

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gamma-glutamyl transpeptidase deficiency	DIS4VHAI	Supportive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Glutathione hydrolase 1 proenzyme (GGT1) decreases the response to substance of Arsenic.	[15]
Carbamazepine	DMZOLBI	Approved	Glutathione hydrolase 1 proenzyme (GGT1) increases the Nephropathy toxic ADR of Carbamazepine.	[16]
Lidocaine	DML4ZOT	Approved	Glutathione hydrolase 1 proenzyme (GGT1) increases the Pyrexia ADR of Lidocaine.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glutathione hydrolase 1 proenzyme (GGT1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Glutathione hydrolase 1 proenzyme (GGT1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[3]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[12]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[13]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Glutathione hydrolase 1 proenzyme (GGT1).	[14]

References

• [1] -glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. Eur J Hum Genet. 2018 Jun;26(6):808-817. doi: 10.1038/s41431-018-0122-6. Epub 2018 Feb 26.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] 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.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [15] Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol Appl Pharmacol. 2008 Jan 15;226(2):199-205. doi: 10.1016/j.taap.2007.09.004. Epub 2007 Sep 15.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.