Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDKD5EH)

• DOT Name: 4-hydroxyphenylpyruvate dioxygenase (HPD)
• Synonyms: EC 1.13.11.27; 4-hydroxyphenylpyruvic acid oxidase; 4HPPD; HPD; HPPDase
• Gene Name: HPD
• Related Disease:
  Tyrosinemia type III
  Hawkinsinuria
• UniProt ID: HPPD_HUMAN
• PDB ID: 3ISQ; 5EC3; 8IM2; 8IM3
• EC Number: 1.13.11.27
• Pfam ID: PF00903
• Sequence:
  MTTYSDKGAKPERGRFLHFHSVTFWVGNAKQAASFYCSKMGFEPLAYRGLETGSREVVSH
  VIKQGKIVFVLSSALNPWNKEMGDHLVKHGDGVKDIAFEVEDCDYIVQKARERGAKIMRE
  PWVEQDKFGKVKFAVLQTYGDTTHTLVEKMNYIGQFLPGYEAPAFMDPLLPKLPKCSLEM
  IDHIVGNQPDQEMVSASEWYLKNLQFHRFWSVDDTQVHTEYSSLRSIVVANYEESIKMPI
  NEPAPGKKKSQIQEYVDYNGGAGVQHIALKTEDIITAIRHLRERGLEFLSVPSTYYKQLR
  EKLKTAKIKVKENIDALEELKILVDYDEKGYLLQIFTKPVQDRPTLFLEVIQRHNHQGFG
  AGNFNSLFKAFEEEQNLRGNLTNMETNGVVPGM
• Function: Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
• KEGG Pathway:
  Ubiquinone and other terpenoid-quinone biosynthesis (hsa00130)
  Tyrosine metabolism (hsa00350)
  Phenylalanine metabolism (hsa00360)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tyrosine catabolism (R-HSA-8963684)
• BioCyc Pathway: MetaCyc:HS08267-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tyrosinemia type III	DISGH7NN	Definitive	Autosomal recessive	[1]
Hawkinsinuria	DISV2HVN	Strong	Autosomal dominant	[2]

9 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 4-hydroxyphenylpyruvate dioxygenase (HPD).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[4]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 4-hydroxyphenylpyruvate dioxygenase (HPD).	[10]

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 4-hydroxyphenylpyruvate dioxygenase (HPD).	[9]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] 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.
• [4] 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.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] 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.
• [9] 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.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.