Details of Drug Off-Target (DOT)

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

• DOT Name: D-amino-acid oxidase (DAO)
• Synonyms: DAAO; DAMOX; DAO; EC 1.4.3.3
• Gene Name: DAO
• Related Disease: Amyotrophic lateral sclerosis
• UniProt ID: OXDA_HUMAN
• PDB ID: 2DU8; 2E48; 2E49; 2E4A; 2E82; 3CUK; 3G3E; 3W4I; 3W4J; 3W4K; 3ZNN; 3ZNO; 3ZNP; 3ZNQ; 4QFC; 4QFD; 5ZJ9; 5ZJA; 6KBP; 7U9S; 7U9U; 8HY5
• EC Number: 1.4.3.3
• Pfam ID: PF01266
• Sequence:
  MRVVVIGAGVIGLSTALCIHERYHSVLQPLDIKVYADRFTPLTTTDVAAGLWQPYLSDPN
  NPQEADWSQQTFDYLLSHVHSPNAENLGLFLISGYNLFHEAIPDPSWKDTVLGFRKLTPR
  ELDMFPDYGYGWFHTSLILEGKNYLQWLTERLTERGVKFFQRKVESFEEVAREGADVIVN
  CTGVWAGALQRDPLLQPGRGQIMKVDAPWMKHFILTHDPERGIYNSPYIIPGTQTVTLGG
  IFQLGNWSELNNIQDHNTIWEGCCRLEPTLKNARIIGERTGFRPVRPQIRLEREQLRTGP
  SNTEVIHNYGHGGYGLTIHWGCALEAAKLFGRILEEKKLSRMPPSHL
• Function: Regulates the level of the neuromodulator D-serine in the brain. Has high activity towards D-DOPA and contributes to dopamine synthesis. Could act as a detoxifying agent which removes D-amino acids accumulated during aging. Acts on a variety of D-amino acids with a preference for those having small hydrophobic side chains followed by those bearing polar, aromatic, and basic groups. Does not act on acidic amino acids.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Arginine and proline metabolism (hsa00330)
  D-Amino acid metabolism (hsa00470)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS03351-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
Amyotrophic lateral sclerosis	DISF7HVM	Moderate	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of D-amino-acid oxidase (DAO).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of D-amino-acid oxidase (DAO).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of D-amino-acid oxidase (DAO).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of D-amino-acid oxidase (DAO).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of D-amino-acid oxidase (DAO).	[5]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the activity of D-amino-acid oxidase (DAO).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of D-amino-acid oxidase (DAO).	[7]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [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] 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.
• [4] 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.
• [5] 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.
• [6] Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia. J Enzyme Inhib Med Chem. 2008 Dec;23(6):901-11. doi: 10.1080/14756360701745478.
• [7] 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.