Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRD3RUJ)

• DOT Name: Kynurenine--oxoglutarate transaminase 1 (KYAT1)
• Synonyms: EC 2.6.1.7; Cysteine-S-conjugate beta-lyase; EC 4.4.1.13; Glutamine transaminase K; GTK; Glutamine--phenylpyruvate transaminase; EC 2.6.1.64; Kynurenine aminotransferase 1; Kynurenine aminotransferase I; KATI; Kynurenine--oxoglutarate transaminase I
• Gene Name: KYAT1
• UniProt ID: KAT1_HUMAN
• PDB ID: 1W7L; 1W7M; 1W7N; 3FVS; 3FVU; 3FVX; 4WLH; 4WLJ; 4WP0
• EC Number: 2.6.1.64; 2.6.1.7; 4.4.1.13
• Pfam ID: PF00155
• Sequence:
  MAKQLQARRLDGIDYNPWVEFVKLASEHDVVNLGQGFPDFPPPDFAVEAFQHAVSGDFML
  NQYTKTFGYPPLTKILASFFGELLGQEIDPLRNVLVTVGGYGALFTAFQALVDEGDEVII
  IEPFFDCYEPMTMMAGGRPVFVSLKPGPIQNGELGSSSNWQLDPMELAGKFTSRTKALVL
  NTPNNPLGKVFSREELELVASLCQQHDVVCITDEVYQWMVYDGHQHISIASLPGMWERTL
  TIGSAGKTFSATGWKVGWVLGPDHIMKHLRTVHQNSVFHCPTQSQAAVAESFEREQLLFR
  QPSSYFVQFPQAMQRCRDHMIRSLQSVGLKPIIPQGSYFLITDISDFKRKMPDLPGAVDE
  PYDRRFVKWMIKNKGLVAIPVSIFYSVPHQKHFDHYIRFCFVKDEATLQAMDEKLRKWKV
  EL
• Function: Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA), an intermediate in the tryptophan catabolic pathway which is also a broad spectrum antagonist of the three ionotropic excitatory amino acid receptors among others. Also metabolizes the cysteine conjugates of certain halogenated alkenes and alkanes to form reactive metabolites. Catalyzes the beta-elimination of S-conjugates and Se-conjugates of L-(seleno)cysteine, resulting in the cleavage of the C-S or C-Se bond.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Tryptophan metabolism (hsa00380)
  Selenocompound metabolism (hsa00450)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Phenylalanine metabolism (R-HSA-8964208)
  Glutamate and glutamine metabolism (R-HSA-8964539)
  Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS10240-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
L-methionine	DME8G1U	Investigative	Kynurenine--oxoglutarate transaminase 1 (KYAT1) increases the amination of L-methionine.	[10]

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 Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[3]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[3]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[6]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[8]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Kynurenine--oxoglutarate transaminase 1 (KYAT1).	[9]

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] 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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [4] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [5] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [6] 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.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate toxicity of the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine in human placental villous trophoblast BeWo cells. Toxicology. 2023 Aug 15;495:153611. doi: 10.1016/j.tox.2023.153611. Epub 2023 Aug 5.
• [10] New insights into the metabolism of organomercury compounds: mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine gama-lyase. Arch Biochem Biophys. 2012 Jan 1;517(1):20-9.