Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAKFN78)

• DOT Name: Dihydroorotate dehydrogenase (DHODH)
• Synonyms: quinone), mitochondrial (DHOdehase; EC 1.3.5.2; Dihydroorotate oxidase
• Gene Name: DHODH
• Related Disease: Postaxial acrofacial dysostosis
• UniProt ID: PYRD_HUMAN
• PDB ID: 1D3G ; 1D3H ; 2B0M ; 2BXV ; 2FPT ; 2FPV ; 2FPY ; 2FQI ; 2PRH ; 2PRL ; 2PRM ; 2WV8 ; 3F1Q ; 3FJ6 ; 3FJL ; 3G0U ; 3G0X ; 3KVJ ; 3KVK ; 3KVL ; 3KVM ; 3U2O ; 3W7R ; 3ZWS ; 3ZWT ; 4IGH ; 4JGD ; 4JS3 ; 4JTS ; 4JTT ; 4JTU ; 4LS0 ; 4LS1 ; 4LS2 ; 4OQV ; 4RK8 ; 4RKA ; 4RLI ; 4RR4 ; 4YLW ; 4ZL1 ; 4ZMG ; 5H2Z ; 5H73 ; 5HIN ; 5HQE ; 5K9C ; 5K9D ; 5MUT ; 5MVC ; 5MVD ; 5TCE ; 5ZF4 ; 5ZF7 ; 5ZF8 ; 5ZF9 ; 5ZFA ; 5ZFB ; 6CJF ; 6CJG ; 6ET4 ; 6FMD ; 6GK0 ; 6IDJ ; 6J3B ; 6J3C ; 6JMD ; 6JME ; 6LP6 ; 6LP7 ; 6LP8 ; 6LZL ; 6M2B ; 6OC0 ; 6OC1 ; 6QU7 ; 6SYP ; 6VND ; 7K2U ; 7Z6C ; 8DHF ; 8DHG ; 8DHH
• EC Number: 1.3.5.2
• Pfam ID: PF01180
• Sequence:
  MAWRHLKKRAQDAVIILGGGGLLFASYLMATGDERFYAEHLMPTLQGLLDPESAHRLAVR
  FTSLGLLPRARFQDSDMLEVRVLGHKFRNPVGIAAGFDKHGEAVDGLYKMGFGFVEIGSV
  TPKPQEGNPRPRVFRLPEDQAVINRYGFNSHGLSVVEHRLRARQQKQAKLTEDGLPLGVN
  LGKNKTSVDAAEDYAEGVRVLGPLADYLVVNVSSPNTAGLRSLQGKAELRRLLTKVLQER
  DGLRRVHRPAVLVKIAPDLTSQDKEDIASVVKELGIDGLIVTNTTVSRPAGLQGALRSET
  GGLSGKPLRDLSTQTIREMYALTQGRVPIIGVGGVSSGQDALEKIRAGASLVQLYTALTF
  WGPPVVGKVKRELEALLKEQGFGGVTDAIGADHRR
• Function: Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Required for UMP biosynthesis via de novo pathway.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Pyrimidine biosynthesis (R-HSA-500753)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Postaxial acrofacial dysostosis	DISGX3R9	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dihydroorotate dehydrogenase (DHODH).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[6]
Atovaquone	DMY4UMW	Approved	Atovaquone decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[9]
Avastin+/-Tarceva	DMA86FL	Phase 3	Avastin+/-Tarceva decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[12]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dihydroorotate dehydrogenase (DHODH).	[15]
1,4-Naphthoquinone	DMTCMH7	Investigative	1,4-Naphthoquinone decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
Plumbagin	DM9BS50	Investigative	Plumbagin decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
Polyporic acid	DMN6Q4E	Investigative	Polyporic acid decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
5,8-Dihydroxy-1,4-naphthoquinone	DMOCEPA	Investigative	5,8-Dihydroxy-1,4-naphthoquinone decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]
Dichloroallyl lawsone	DMXGV63	Investigative	Dichloroallyl lawsone decreases the activity of Dihydroorotate dehydrogenase (DHODH).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dihydroorotate dehydrogenase (DHODH).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dihydroorotate dehydrogenase (DHODH).	[11]

References

• [1] Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [8] Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact. 2000 Jan 3;124(1):61-76.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [12] Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol. 1998 Nov 1;56(9):1259-64. doi: 10.1016/s0006-2952(98)00145-2.
• [13] Metabolomics profiles delineate uridine deficiency contributes to mitochondria-mediated apoptosis induced by celastrol in human acute promyelocytic leukemia cells. Oncotarget. 2016 Jul 19;7(29):46557-46572.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.