Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOUBD05)

• DOT Name: Pyridoxine-5'-phosphate oxidase (PNPO)
• Synonyms: EC 1.4.3.5; Pyridoxamine-phosphate oxidase
• Gene Name: PNPO
• Related Disease: Pyridoxal phosphate-responsive seizures
• UniProt ID: PNPO_HUMAN
• PDB ID: 1NRG; 3HY8; 6H00
• EC Number: 1.4.3.5
• Pfam ID: PF10590 ; PF01243
• Sequence:
  MTCWLRGVTATFGRPAEWPGYLSHLCGRSAAMDLGPMRKSYRGDREAFEETHLTSLDPVK
  QFAAWFEEAVQCPDIGEANAMCLATCTRDGKPSARMLLLKGFGKDGFRFFTNFESRKGKE
  LDSNPFASLVFYWEPLNRQVRVEGPVKKLPEEEAECYFHSRPKSSQIGAVVSHQSSVIPD
  REYLRKKNEELEQLYQDQEVPKPKSWGGYVLYPQVMEFWQGQTNRLHDRIVFRRGLPTGD
  SPLGPMTHRGEEDWLYERLAP
• Function: Catalyzes the oxidation of either pyridoxine 5'-phosphate (PNP) or pyridoxamine 5'-phosphate (PMP) into pyridoxal 5'-phosphate (PLP).
• Tissue Specificity: Ubiquitous. Expressed in liver, brain, lung, prostate and stomach (at protein level).
• KEGG Pathway:
  Vitamin B6 metabolism (hsa00750)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Vitamin B6 activation to pyridoxal phosphate (R-HSA-964975)
• BioCyc Pathway: MetaCyc:HS03105-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
Pyridoxal phosphate-responsive seizures	DIS3AMWI	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Pyridoxine-5'-phosphate oxidase (PNPO) decreases the response to substance of Arsenic trioxide.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pyridoxine-5'-phosphate oxidase (PNPO).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pyridoxine-5'-phosphate oxidase (PNPO).	[12]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Proteomic profiling reveals that resveratrol inhibits HSP27 expression and sensitizes breast cancer cells to doxorubicin therapy. PLoS One. 2013 May 27;8(5):e64378.
• [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] 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.
• [12] 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.
• [13] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.