Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT75GZ3K)

• DOT Name: Protoporphyrinogen oxidase (PPOX)
• Synonyms: PPO; EC 1.3.3.4
• Gene Name: PPOX
• Related Disease: Variegate porphyria
• UniProt ID: PPOX_HUMAN
• PDB ID: 3NKS; 4IVM; 4IVO
• EC Number: 1.3.3.4
• Pfam ID: PF01593
• Sequence:
  MGRTVVVLGGGISGLAASYHLSRAPCPPKVVLVESSERLGGWIRSVRGPNGAIFELGPRG
  IRPAGALGARTLLLVSELGLDSEVLPVRGDHPAAQNRFLYVGGALHALPTGLRGLLRPSP
  PFSKPLFWAGLRELTKPRGKEPDETVHSFAQRRLGPEVASLAMDSLCRGVFAGNSRELSI
  RSCFPSLFQAEQTHRSILLGLLLGAGRTPQPDSALIRQALAERWSQWSLRGGLEMLPQAL
  ETHLTSRGVSVLRGQPVCGLSLQAEGRWKVSLRDSSLEADHVISAIPASVLSELLPAEAA
  PLARALSAITAVSVAVVNLQYQGAHLPVQGFGHLVPSSEDPGVLGIVYDSVAFPEQDGSP
  PGLRVTVMLGGSWLQTLEASGCVLSQELFQQRAQEAAATQLGLKEMPSHCLVHLHKNCIP
  QYTLGHWQKLESARQFLTAHRLPLTLAGASYEGVAVNDCIESGRQAAVSVLGTEPNS
• Function: Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS07011-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
Variegate porphyria	DIS8OK5W	Definitive	Semidominant	[1]

10 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 Protoporphyrinogen oxidase (PPOX).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protoporphyrinogen oxidase (PPOX).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protoporphyrinogen oxidase (PPOX).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protoporphyrinogen oxidase (PPOX).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protoporphyrinogen oxidase (PPOX).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protoporphyrinogen oxidase (PPOX).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Protoporphyrinogen oxidase (PPOX).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protoporphyrinogen oxidase (PPOX).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protoporphyrinogen oxidase (PPOX).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protoporphyrinogen oxidase (PPOX).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] 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.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] 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.
• [10] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.