Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDJYEO7)

• DOT Name: Glutathione hydrolase 5 proenzyme (GGT5)
• Synonyms: EC 3.4.19.13; Gamma-glutamyl transpeptidase-related enzyme; GGT-rel; Gamma-glutamyltransferase 5; GGT 5; EC 2.3.2.2; Gamma-glutamyltransferase-like activity 1; Gamma-glutamyltranspeptidase 5; Leukotriene-C4 hydrolase; EC 3.4.19.14
• Gene Name: GGT5
• UniProt ID: GGT5_HUMAN
• EC Number: 2.3.2.2; 3.4.19.13; 3.4.19.14
• Pfam ID: PF01019
• Sequence:
  MARGYGATVSLVLLGLGLALAVIVLAVVLSRHQAPCGPQAFAHAAVAADSKVCSDIGRAI
  LQQQGSPVDATIAALVCTSVVNPQSMGLGGGVIFTIYNVTTGKVEVINARETVPASHAPS
  LLDQCAQALPLGTGAQWIGVPGELRGYAEAHRRHGRLPWAQLFQPTIALLRGGHVVAPVL
  SRFLHNSILRPSLQASTLRQLFFNGTEPLRPQDPLPWPALATTLETVATEGVEVFYTGRL
  GQMLVEDIAKEGSQLTLQDLAKFQPEVVDALEVPLGDYTLYSPPPPAGGAILSFILNVLR
  GFNFSTESMARPEGRVNVYHHLVETLKFAKGQRWRLGDPRSHPKLQNASRDLLGETLAQL
  IRQQIDGRGDHQLSHYSLAEAWGHGTGTSHVSVLGEDGSAVAATSTINTPFGAMVYSPRT
  GIILNNELLDLCERCPRGSGTTPSPVSGDRVGGAPGRCWPPVPGERSPSSMVPSILINKA
  QGSKLVIGGAGGELIISAVAQAIMSKLWLGFDLRAAIAAPILHVNSKGCVEYEPNFSQEV
  QRGLQDRGQNQTQRPFFLNVVQAVSQEGACVYAVSDLRKSGEAAGY
• Function: Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate such as leukotriene C4. Does not cleaves gamma-glutamyl compounds such as gamma-glutamyl leucine. May also catalyze a transpeptidation reaction in addition to the hydrolysis reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound. Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses.
• 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)
  LTC4-CYSLTR mediated IL4 production (R-HSA-9664535)
  Paracetamol ADME (R-HSA-9753281)
  Glutathione synthesis and recycling (R-HSA-174403)
• BioCyc Pathway: MetaCyc:HS01949-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 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 5 proenzyme (GGT5).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[6]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[7]
Fluticasone propionate	DMRWLB2	Approved	Fluticasone propionate increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[8]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[9]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Glutathione hydrolase 5 proenzyme (GGT5).	[10]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [7] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [8] A novel pharmacologic action of glucocorticosteroids on leukotriene C4 catabolism. J Allergy Clin Immunol. 2001 Jul;108(1):122-4.
• [9] 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.
• [10] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.