Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK9Y6SG)

• DOT Name: 3-hydroxyanthranilate 3,4-dioxygenase (HAAO)
• Synonyms: EC 1.13.11.6; 3-hydroxyanthranilate oxygenase; 3-HAO; h3HAO; 3-hydroxyanthranilic acid dioxygenase; HAD
• Gene Name: HAAO
• Related Disease:
  Vertebral, cardiac, renal, and limb defects syndrome 1
  Congenital vertebral-cardiac-renal anomalies syndrome
• UniProt ID: 3HAO_HUMAN
• PDB ID: 2QNK; 5TK5; 5TKQ
• EC Number: 1.13.11.6
• Pfam ID: PF06052
• Sequence:
  MERRLGVRAWVKENRGSFQPPVCNKLMHQEQLKVMFIGGPNTRKDYHIEEGEEVFYQLEG
  DMVLRVLEQGKHRDVVIRQGEIFLLPARVPHSPQRFANTVGLVVERRRLETELDGLRYYV
  GDTMDVLFEKWFYCKDLGTQLAPIIQEFFSSEQYRTGKPIPDQLLKEPPFPLSTRSIMEP
  MSLDAWLDSHHRELQAGTPLSLFGDTYETQVIAYGQGSSEGLRQNVDVWLWQLEGSSVVT
  MGGRRLSLAPDDSLLVLAGTSYAWERTQGSVALSVTQDPACKKPLG
• Function: Catalyzes the oxidative ring opening of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde, which spontaneously cyclizes to quinolinate.
• KEGG Pathway:
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS08749-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Vertebral, cardiac, renal, and limb defects syndrome 1	DIS0MCIQ	Definitive	Autosomal recessive	[1]
Congenital vertebral-cardiac-renal anomalies syndrome	DISR2YKP	Supportive	Autosomal recessive	[2]

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 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[3]

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 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[7]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[8]
Aciclovir	DMYLOVR	Approved	Aciclovir decreases the activity of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 3-hydroxyanthranilate 3,4-dioxygenase (HAAO).	[11]

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] NAD Deficiency, Congenital Malformations, and Niacin Supplementation. N Engl J Med. 2017 Aug 10;377(6):544-552.
• [3] 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.
• [4] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [9] Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid. Life Sci. 2007 Feb 13;80(10):918-25.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.