Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT30YKV0)

• DOT Name: Amine oxidase 3 (AOC3)
• Synonyms: EC 1.4.3.21; Amine oxidase copper-containing 3; Copper amine oxidase; HPAO; Semicarbazide-sensitive amine oxidase; SSAO; Vascular adhesion protein 1; VAP-1
• Gene Name: AOC3
• UniProt ID: AOC3_HUMAN
• PDB ID: 1PU4; 1US1; 2C10; 2C11; 2Y73; 2Y74; 3ALA; 4BTW; 4BTX; 4BTY
• EC Number: 1.4.3.21
• Pfam ID: PF01179 ; PF02727 ; PF02728
• Sequence:
  MNQKTILVLLILAVITIFALVCVLLVGRGGDGGEPSQLPHCPSVSPSAQPWTHPGQSQLF
  ADLSREELTAVMRFLTQRLGPGLVDAAQARPSDNCVFSVELQLPPKAAALAHLDRGSPPP
  AREALAIVFFGRQPQPNVSELVVGPLPHPSYMRDVTVERHGGPLPYHRRPVLFQEYLDID
  QMIFNRELPQASGLLHHCCFYKHRGRNLVTMTTAPRGLQSGDRATWFGLYYNISGAGFFL
  HHVGLELLVNHKALDPARWTIQKVFYQGRYYDSLAQLEAQFEAGLVNVVLIPDNGTGGSW
  SLKSPVPPGPAPPLQFYPQGPRFSVQGSRVASSLWTFSFGLGAFSGPRIFDVRFQGERLV
  YEISLQEALAIYGGNSPAAMTTRYVDGGFGMGKYTTPLTRGVDCPYLATYVDWHFLLESQ
  APKTIRDAFCVFEQNQGLPLRRHHSDLYSHYFGGLAETVLVVRSMSTLLNYDYVWDTVFH
  PSGAIEIRFYATGYISSAFLFGATGKYGNQVSEHTLGTVHTHSAHFKVDLDVAGLENWVW
  AEDMVFVPMAVPWSPEHQLQRLQVTRKLLEMEEQAAFLVGSATPRYLYLASNHSNKWGHP
  RGYRIQMLSFAGEPLPQNSSMARGFSWERYQLAVTQRKEEEPSSSSVFNQNDPWAPTVDF
  SDFINNETIAGKDLVAWVTAGFLHIPHAEDIPNTVTVGNGVGFFLRPYNFFDEDPSFYSA
  DSIYFRGDQDAGACEVNPLACLPQAAACAPDLPAFSHGGFSHN
• Function: Catalyzes the oxidative deamination of primary amines to the corresponding aldehydes with the concomitant production of hydrogen peroxide and ammonia. Has a preference for the primary monoamines methylamine and benzylamine. Could also act on 2-phenylethylamine but much less efficiently. At endothelial cells surface can also function as a cell adhesion protein that participates in lymphocyte extravasation and recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin-independent fashion ; [Isoform 2]: Has no semicarbazide-sensitive amine oxidase (SSAO) activity.
• Tissue Specificity: Strongly expressed on the high endothelial venules of peripheral lymph nodes and on hepatic endothelia. Also highly expressed in appendix, lung and small intestine. Expressed also in adipose tissue, in bone marrow, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, spleen and testis. Isoform 2 seems to be the predominant transcript in fetal kidneys, fetal cartilage and fetal tonsils. The highest relative expression of isoform 2 occurs in skeletal muscle, heart, pancreas, kidney, and lung.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Tyrosine metabolism (hsa00350)
  Phenylalanine metabolism (hsa00360)
  beta-Alanine metabolism (hsa00410)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phase I - Functionalization of compounds (R-HSA-211945)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Amine oxidase 3 (AOC3) increases the chemical synthesis of Hydrogen peroxide.	[14]
Ammonia	DMOEVK6	Approved	Amine oxidase 3 (AOC3) increases the chemical synthesis of Ammonia.	[14]

12 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 Amine oxidase 3 (AOC3).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Amine oxidase 3 (AOC3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Amine oxidase 3 (AOC3).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Amine oxidase 3 (AOC3).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Amine oxidase 3 (AOC3).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Amine oxidase 3 (AOC3).	[6]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Amine oxidase 3 (AOC3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Amine oxidase 3 (AOC3).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Amine oxidase 3 (AOC3).	[10]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Amine oxidase 3 (AOC3).	[12]
HYDRAZINECARBOXAMIDE	DMARWG5	Investigative	HYDRAZINECARBOXAMIDE decreases the activity of Amine oxidase 3 (AOC3).	[13]
N'-(2-phenylallyl)hydrazine hydrochloride	DMBR1MX	Investigative	N'-(2-phenylallyl)hydrazine hydrochloride decreases the activity of Amine oxidase 3 (AOC3).	[14]

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 decreases the methylation of Amine oxidase 3 (AOC3).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Amine oxidase 3 (AOC3).	[11]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [5] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [6] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [7] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [8] 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.
• [9] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [13] Amine metabolism: a novel path to coronary artery vasospasm. Toxicol Appl Pharmacol. 2001 Sep 1;175(2):149-59.
• [14] Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase. J Pharmacol Exp Ther. 2005 Nov;315(2):553-62. doi: 10.1124/jpet.105.089649. Epub 2005 Aug 4.