Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3MRMM9)

• DOT Name: Kynurenine 3-monooxygenase (KMO)
• Synonyms: EC 1.14.13.9; Kynurenine 3-hydroxylase
• Gene Name: KMO
• Related Disease: Pellagra
• UniProt ID: KMO_HUMAN
• PDB ID: 5X68
• EC Number: 1.14.13.9
• Pfam ID: PF01494
• Sequence:
  MDSSVIQRKKVAVIGGGLVGSLQACFLAKRNFQIDVYEAREDTRVATFTRGRSINLALSH
  RGRQALKAVGLEDQIVSQGIPMRARMIHSLSGKKSAIPYGTKSQYILSVSRENLNKDLLT
  AAEKYPNVKMHFNHRLLKCNPEEGMITVLGSDKVPKDVTCDLIVGCDGAYSTVRSHLMKK
  PRFDYSQQYIPHGYMELTIPPKNGDYAMEPNYLHIWPRNTFMMIALPNMNKSFTCTLFMP
  FEEFEKLLTSNDVVDFFQKYFPDAIPLIGEKLLVQDFFLLPAQPMISVKCSSFHFKSHCV
  LLGDAAHAIVPFFGQGMNAGFEDCLVFDELMDKFSNDLSLCLPVFSRLRIPDDHAISDLS
  MYNYIEMRAHVNSSWFIFQKNMERFLHAIMPSTFIPLYTMVTFSRIRYHEAVQRWHWQKK
  VINKGLFFLGSLIAISSTYLLIHYMSPRSFLRLRRPWNWIAHFRNTTCFPAKAVDSLEQI
  SNLISR
• Function: Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract (Probable).
• Tissue Specificity: Highest levels in placenta and liver. Detectable in kidney.
• KEGG Pathway:
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS04082-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pellagra	DISAVNWB	No Known	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Kynurenine 3-monooxygenase (KMO) increases the response to substance of Cytarabine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Kynurenine 3-monooxygenase (KMO).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kynurenine 3-monooxygenase (KMO).	[11]

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 3-monooxygenase (KMO).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kynurenine 3-monooxygenase (KMO).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kynurenine 3-monooxygenase (KMO).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kynurenine 3-monooxygenase (KMO).	[6]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Kynurenine 3-monooxygenase (KMO).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Kynurenine 3-monooxygenase (KMO).	[8]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Kynurenine 3-monooxygenase (KMO).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kynurenine 3-monooxygenase (KMO).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [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] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [9] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [10] 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.
• [11] 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.
• [12] Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.