Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7HVXRL)

• DOT Name: Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX)
• Synonyms: EC 1.5.3.13; Polyamine oxidase
• Gene Name: PAOX
• UniProt ID: PAOX_HUMAN
• EC Number: 1.5.3.13
• Pfam ID: PF01593
• Sequence:
  MESTGSVGEAPGGPRVLVVGGGIAGLGAAQRLCGHSAFPHLRVLEATARAGGRIRSERCF
  GGVVEVGAHWIHGPSRGNPVFQLAAEYGLLGEKELSQENQLVETGGHVGLPSVSYASSGA
  SVSLQLVAEMATLFYGLIDQTREFLHAAETPVPSVGEYLKKEIGQHVAGWTEDEETRKLK
  LAVLNSFFNLECCVSGTHSMDLVALAPFGEYTVLPGLDCTFSKGYQGLTNCMMAALPEDT
  VVFEKPVKTIHWNGSFQEAAFPGETFPVSVECEDGDRFPAHHVIVTVPLGFLREHLDTFF
  DPPLPAEKAEAIRKIGFGTNNKIFLEFEEPFWEPDCQLIQLVWEDTSPLEDAAPELQDAW
  FRKLIGFVVLPAFASVHVLCGFIAGLESEFMETLSDEEVLLCLTQVLRRVTGNPRLPAPK
  SVLRSRWHSAPYTRGSYSYVAVGSTGGDLDLLAQPLPADGAGAQLQILFAGEATHRTFYS
  TTHGALLSGWREADRLLSLWAPQVQQPRPRL
• Function: Flavoenzyme which catalyzes the oxidation of N(1)-acetylspermine to spermidine and is thus involved in the polyamine back-conversion. Can also oxidize N(1)-acetylspermidine to putrescine. Substrate specificity: N(1)-acetylspermine = N(1)-acetylspermidine > N(1),N(12)-diacylspermine >> spermine. Does not oxidize spermidine. Plays an important role in the regulation of polyamine intracellular concentration and has the potential to act as a determinant of cellular sensitivity to the antitumor polyamine analogs.
• Tissue Specificity: Widely expressed. Not detected in spleen. Expressed at lower level in neoplastic tissues.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Interconversion of polyamines (R-HSA-351200)
  Peroxisomal protein import (R-HSA-9033241)
  PAOs oxidise polyamines to amines (R-HSA-141334)

Molecular Interaction Atlas (MIA) of This DOT

2 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 Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[3]

9 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 Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[7]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Peroxisomal N(1)-acetyl-spermine/spermidine oxidase (PAOX).	[11]

References

• [1] 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.
• [2] 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.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.