Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRC220K)

• DOT Name: Diamine oxidase (AOC1)
• Synonyms: Diamine oxidase; EC 1.4.3.22; Amiloride-binding protein; Amiloride-binding protein 1; Amine oxidase copper domain-containing protein 1; Histaminase; Kidney amine oxidase; KAO; KDAO
• Gene Name: AOC1
• UniProt ID: AOC1_HUMAN
• PDB ID: 3HI7; 3HIG; 3HII; 3K5T; 3MPH
• EC Number: 1.4.3.22
• Pfam ID: PF01179 ; PF02727 ; PF02728
• Sequence:
  MPALGWAVAAILMLQTAMAEPSPGTLPRKAGVFSDLSNQELKAVHSFLWSKKELRLQPSS
  TTTMAKNTVFLIEMLLPKKYHVLRFLDKGERHPVREARAVIFFGDQEHPNVTEFAVGPLP
  GPCYMRALSPRPGYQSSWASRPISTAEYALLYHTLQEATKPLHQFFLNTTGFSFQDCHDR
  CLAFTDVAPRGVASGQRRSWLIIQRYVEGYFLHPTGLELLVDHGSTDAGHWAVEQVWYNG
  KFYGSPEELARKYADGEVDVVVLEDPLPGGKGHDSTEEPPLFSSHKPRGDFPSPIHVSGP
  RLVQPHGPRFRLEGNAVLYGGWSFAFRLRSSSGLQVLNVHFGGERIAYEVSVQEAVALYG
  GHTPAGMQTKYLDVGWGLGSVTHELAPGIDCPETATFLDTFHYYDADDPVHYPRALCLFE
  MPTGVPLRRHFNSNFKGGFNFYAGLKGQVLVLRTTSTVYNYDYIWDFIFYPNGVMEAKMH
  ATGYVHATFYTPEGLRHGTRLHTHLIGNIHTHLVHYRVDLDVAGTKNSFQTLQMKLENIT
  NPWSPRHRVVQPTLEQTQYSWERQAAFRFKRKLPKYLLFTSPQENPWGHKRTYRLQIHSM
  ADQVLPPGWQEEQAITWARYPLAVTKYRESELCSSSIYHQNDPWHPPVVFEQFLHNNENI
  ENEDLVAWVTVGFLHIPHSEDIPNTATPGNSVGFLLRPFNFFPEDPSLASRDTVIVWPRD
  NGPNYVQRWIPEDRDCSMPPPFSYNGTYRPV
• Function: Catalyzes the oxidative deamination of primary amines to the corresponding aldehydes with the concomitant production of hydrogen peroxide and ammonia. Its preferred substrates are the diamines histamine and 1-methylhistamine and it could therefore play a role in allergic and immune responses. Has a broad specificity for diamines and can also act on cadaverine and putrescine, two products of amino acid catabolism. It could also act on polyamines, like spermidine and spermine though less efficiently, and regulate various biological processes.
• Tissue Specificity: Widely expressed with higher expression in placenta and kidney.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Histidine metabolism (hsa00340)
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Phase I - Functionalization of compounds (R-HSA-211945)
• BioCyc Pathway: MetaCyc:HS00083-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Diamine oxidase (AOC1) affects the response to substance of Methotrexate.	[10]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Putrescine	DMWE6V1	Discontinued in Phase 2	Diamine oxidase (AOC1) increases the degradation of Putrescine.	[5]
N-[3H]methylhistamine	DM0CI4L	Investigative	Diamine oxidase (AOC1) increases the metabolism of N-[3H]methylhistamine.	[11]

10 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 Diamine oxidase (AOC1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Diamine oxidase (AOC1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Diamine oxidase (AOC1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Diamine oxidase (AOC1).	[4]
Amiloride	DMRTSGP	Approved	Amiloride decreases the activity of Diamine oxidase (AOC1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diamine oxidase (AOC1).	[6]
Aminoguanidine	DMJQDUC	Phase 1	Aminoguanidine decreases the activity of Diamine oxidase (AOC1).	[5]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Diamine oxidase (AOC1).	[7]
5'-(N-ethyl-N-isopropyl)amiloride	DM3TPMO	Investigative	5'-(N-ethyl-N-isopropyl)amiloride decreases the activity of Diamine oxidase (AOC1).	[5]
phenamil	DMJLUFM	Investigative	phenamil decreases the activity of Diamine oxidase (AOC1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Diamine oxidase (AOC1).	[8]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzamil	DM57SVW	Investigative	Benzamil affects the binding of Diamine oxidase (AOC1).	[9]

References

• [1] 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.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [5] Diamine oxidase is the amiloride-binding protein and is inhibited by amiloride analogues. J Biol Chem. 1994 Apr 1;269(13):9921-5.
• [6] 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.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] 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.
• [9] Human kidney amiloride-binding protein: cDNA structure and functional expression. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7347-51. doi: 10.1073/pnas.87.19.7347.
• [10] 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.
• [11] Human kidney diamine oxidase: heterologous expression, purification, and characterization. J Biol Inorg Chem. 2002 Jun;7(6):565-79.