Details of Drug Off-Target (DOT)

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

• DOT Name: Dihydropteridine reductase (QDPR)
• Synonyms: EC 1.5.1.34; HDHPR; Quinoid dihydropteridine reductase; Short chain dehydrogenase/reductase family 33C member 1
• Gene Name: QDPR
• Related Disease:
  Dihydropteridine reductase deficiency
  Intellectual disability
  LennoxGastaut syndrome
  Malignant hyperthermia of anesthesia
  Myopathy
  Vitiligo
  Treacher-Collins syndrome
  High blood pressure
  Classic phenylketonuria
  Dystonia
  Hyperphenylalaninemia
  Nervous system disease
  Parkinson disease
  Phenylketonuria
  Status epilepticus seizure
• UniProt ID: DHPR_HUMAN
• PDB ID: 1HDR
• EC Number: 1.5.1.34
• Pfam ID: PF00106
• Sequence:
  MAAAAAAGEARRVLVYGGRGALGSRCVQAFRARNWWVASVDVVENEEASASIIVKMTDSF
  TEQADQVTAEVGKLLGEEKVDAILCVAGGWAGGNAKSKSLFKNCDLMWKQSIWTSTISSH
  LATKHLKEGGLLTLAGAKAALDGTPGMIGYGMAKGAVHQLCQSLAGKNSGMPPGAAAIAV
  LPVTLDTPMNRKSMPEADFSSWTPLEFLVETFHDWITGKNRPSSGSLIQVVTTEGRTELT
  PAYF
• Function: Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phenylalanine metabolism (R-HSA-8964208)
• BioCyc Pathway: MetaCyc:HS07746-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dihydropteridine reductase deficiency	DIS1IC3E	Definitive	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[2]
LennoxGastaut syndrome	DISOTGO5	Strong	Genetic Variation	[3]
Malignant hyperthermia of anesthesia	DISYC9XI	Strong	Genetic Variation	[4]
Myopathy	DISOWG27	Strong	Biomarker	[4]
Vitiligo	DISR05SL	Strong	Biomarker	[5]
Treacher-Collins syndrome	DIS2GXZ1	moderate	Genetic Variation	[6]
High blood pressure	DISY2OHH	Disputed	Biomarker	[7]
Classic phenylketonuria	DISLU64N	Limited	Biomarker	[8]
Dystonia	DISJLFGW	Limited	Biomarker	[9]
Hyperphenylalaninemia	DISCQU4G	Limited	Biomarker	[8]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[10]
Phenylketonuria	DISCU56J	Limited	Biomarker	[8]
Status epilepticus seizure	DISY3BIC	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dihydropteridine reductase (QDPR).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dihydropteridine reductase (QDPR).	[23]

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 Dihydropteridine reductase (QDPR).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dihydropteridine reductase (QDPR).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dihydropteridine reductase (QDPR).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dihydropteridine reductase (QDPR).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dihydropteridine reductase (QDPR).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydropteridine reductase (QDPR).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Dihydropteridine reductase (QDPR).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the activity of Dihydropteridine reductase (QDPR).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dihydropteridine reductase (QDPR).	[21]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Dihydropteridine reductase (QDPR).	[22]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Dihydropteridine reductase (QDPR).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dihydropteridine reductase (QDPR).	[24]

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] Serum prolactin as a tool for the follow-up of treated DHPR-deficient patients.J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S193-7. doi: 10.1007/s10545-007-0788-3. Epub 2008 Apr 15.
• [3] Experience with hyperphenylalaninemia in a developing country: unusual clinical manifestations and a novel gene mutation.J Child Neurol. 2011 Feb;26(2):142-6. doi: 10.1177/0883073810375116. Epub 2010 Sep 7.
• [4] Dynamic alterations in myoplasmic Ca2+ in malignant hyperthermia and central core disease.Biochem Biophys Res Commun. 2004 Oct 1;322(4):1256-66. doi: 10.1016/j.bbrc.2004.08.031.
• [5] Perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo: more evidence for H2O2 stress.J Invest Dermatol. 2004 Feb;122(2):307-13. doi: 10.1046/j.0022-202X.2004.22230.x.
• [6] Chromosomal deletion 4p15.32----p14 in a Treacher Collins syndrome patient: exclusion of the disease locus from and mapping of anonymous DNA sequences to this region.Genomics. 1991 Sep;11(1):188-92. doi: 10.1016/0888-7543(91)90117-w.
• [7] Diminished expression of dihydropteridine reductase is a potent biomarker for hypertensive vessels.Proteomics. 2009 Nov;9(21):4851-8. doi: 10.1002/pmic.200800973.
• [8] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [9] Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3.Am J Hum Genet. 2000 Feb;66(2):445-52. doi: 10.1086/302744.
• [10] Genetic causes of Parkinson's disease in the Maltese: a study of selected mutations in LRRK2, MTHFR, QDPR and SPR.BMC Med Genet. 2016 Sep 9;17(1):65. doi: 10.1186/s12881-016-0327-x.
• [11] Proteome changes associated with hippocampal MRI abnormalities in the lithium pilocarpine-induced model of convulsive status epilepticus.Proteomics. 2007 Apr;7(8):1336-44. doi: 10.1002/pmic.200601027.
• [12] 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.
• [13] 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.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [18] 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.
• [19] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [20] [Early neurotoxicity of high-dose of methotrexate and tetrahydrobiopterin deficiency]. Arch Fr Pediatr. 1991 Dec;48(10):719-22.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [23] 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.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.