Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4U2QK)

• DOT Name: Kynurenine--oxoglutarate transaminase 3 (KYAT3)
• Synonyms: EC 2.6.1.7; Cysteine-S-conjugate beta-lyase 2; EC 4.4.1.13; Kynurenine aminotransferase 3; Kynurenine aminotransferase III; KATIII; Kynurenine--glyoxylate transaminase; EC 2.6.1.63; Kynurenine--oxoglutarate transaminase III
• Gene Name: KYAT3
• Related Disease:
  Primary hyperoxaluria
  Advanced cancer
  Attention deficit hyperactivity disorder
  Crohn disease
  leukaemia
  Leukemia
  Major depressive disorder
  Schizophrenia
  Ulcerative colitis
  Venous thromboembolism
• UniProt ID: KAT3_HUMAN
• EC Number: 2.6.1.63; 2.6.1.7; 4.4.1.13
• Pfam ID: PF00155
• Sequence:
  MFLAQRSLCSLSGRAKFLKTISSSKILGFSTSAKMSLKFTNAKRIEGLDSNVWIEFTKLA
  ADPSVVNLGQGFPDISPPTYVKEELSKIAAIDSLNQYTRGFGHPSLVKALSYLYEKLYQK
  QIDSNKEILVTVGAYGSLFNTIQALIDEGDEVILIVPFYDCYEPMVRMAGATPVFIPLRS
  KPVYGKRWSSSDWTLDPQELESKFNSKTKAIILNTPHNPLGKVYNREELQVIADLCIKYD
  TLCISDEVYEWLVYSGNKHLKIATFPGMWERTITIGSAGKTFSVTGWKLGWSIGPNHLIK
  HLQTVQQNTIYTCATPLQEALAQAFWIDIKRMDDPECYFNSLPKELEVKRDRMVRLLESV
  GLKPIVPDGGYFIIADVSLLDPDLSDMKNNEPYDYKFVKWMTKHKKLSAIPVSAFCNSET
  KSQFEKFVRFCFIKKDSTLDAAEEIIKAWSVQKS
• 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. May catalyze 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. Has transaminase activity towards L-kynurenine, tryptophan, phenylalanine, serine, cysteine, methionine, histidine, glutamine and asparagine with glyoxylate as an amino group acceptor (in vitro). Has lower activity with 2-oxoglutarate as amino group acceptor (in vitro).
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Tryptophan metabolism (hsa00380)
  Selenocompound metabolism (hsa00450)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS06422-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary hyperoxaluria	DIS0L16N	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[4]
leukaemia	DISS7D1V	Strong	Biomarker	[5]
Leukemia	DISNAKFL	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[7]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[4]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Kynurenine--oxoglutarate transaminase 3 (KYAT3) affects the response to substance of Acetaminophen.	[19]
Mitomycin	DMH0ZJE	Approved	Kynurenine--oxoglutarate transaminase 3 (KYAT3) affects the response to substance of Mitomycin.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[18]

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 increases the methylation of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Kynurenine--oxoglutarate transaminase 3 (KYAT3).	[16]

References

• [1] Metabolism of Oxalate in Humans: A Potential Role Kynurenine Aminotransferase/Glutamine Transaminase/Cysteine Conjugate Betalyase Plays in Hyperoxaluria.Curr Med Chem. 2019;26(26):4944-4963. doi: 10.2174/0929867326666190325095223.
• [2] Differentiation Therapy Targeting the -Catenin/CBP Interaction in Pancreatic Cancer.Cancers (Basel). 2018 Mar 29;10(4):95. doi: 10.3390/cancers10040095.
• [3] Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity.Am J Med Genet B Neuropsychiatr Genet. 2014 Dec;165B(8):691-704. doi: 10.1002/ajmg.b.32275. Epub 2014 Oct 25.
• [4] Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease.Therap Adv Gastroenterol. 2019 Oct 19;12:1756284819881304. doi: 10.1177/1756284819881304. eCollection 2019.
• [5] Hypoxia selects for a quiescent, CML stem/leukemia initiating-like population dependent on CBP/catenin transcription.Curr Mol Pharmacol. 2013 Nov;6(3):204-10. doi: 10.2174/1874467207666140219121219.
• [6] The kynurenine pathway in major depression: haplotype analysis of three related functional candidate genes.Psychiatry Res. 2011 Aug 15;188(3):355-60. doi: 10.1016/j.psychres.2011.03.012. Epub 2011 Apr 13.
• [7] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [8] Metabolomic association between venous thromboembolism in critically ill trauma patients and kynurenine pathway of tryptophan metabolism.Thromb Res. 2018 May;165:6-13. doi: 10.1016/j.thromres.2018.03.003. Epub 2018 Mar 8.
• [9] 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.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.
• [20] 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.