Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPP4UH5)

• DOT Name: Uroporphyrinogen decarboxylase
• Synonyms: UPD; URO-D; EC 4.1.1.37
• Gene Name: UROD
• Related Disease:
  UROD-related inherited porphyria
  Familial porphyria cutanea tarda
  Hepatoerythropoietic porphyria
• UniProt ID: DCUP_HUMAN
• PDB ID: 1JPH; 1JPI; 1JPK; 1R3Q; 1R3R; 1R3S; 1R3T; 1R3V; 1R3W; 1R3Y; 1URO; 2Q6Z; 2Q71; 3GVQ; 3GVR; 3GVV; 3GVW; 3GW0; 3GW3
• EC Number: 4.1.1.37
• Pfam ID: PF01208
• Sequence:
  MEANGLGPQGFPELKNDTFLRAAWGEETDYTPVWCMRQAGRYLPEFRETRAAQDFFSTCR
  SPEACCELTLQPLRRFPLDAAIIFSDILVVPQALGMEVTMVPGKGPSFPEPLREEQDLER
  LRDPEVVASELGYVFQAITLTRQRLAGRVPLIGFAGAPWTLMTYMVEGGGSSTMAQAKRW
  LYQRPQASHQLLRILTDALVPYLVGQVVAGAQALQLFESHAGHLGPQLFNKFALPYIRDV
  AKQVKARLREAGLAPVPMIIFAKDGHFALEELAQAGYEVVGLDWTVAPKKARECVGKTVT
  LQGNLDPCALYASEEEIGQLVKQMLDDFGPHRYIANLGHGLYPDMDPEHVGAFVDAVHKH
  SRLLRQN
• Function: Catalyzes the sequential decarboxylation of the four acetate side chains of uroporphyrinogen to form coproporphyrinogen and participates in the fifth step in the heme biosynthetic pathway. Isomer I or isomer III of uroporphyrinogen may serve as substrate, but only coproporphyrinogen III can ultimately be converted to heme. In vitro also decarboxylates pentacarboxylate porphyrinogen I.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS04993-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
UROD-related inherited porphyria	DISI1WCX	Definitive	Semidominant	[1]
Familial porphyria cutanea tarda	DISYJ053	Strong	Autosomal dominant	[2]
Hepatoerythropoietic porphyria	DISUQQ6J	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Uroporphyrinogen decarboxylase decreases the response to substance of Cisplatin.	[15]
Fluorouracil	DMUM7HZ	Approved	Uroporphyrinogen decarboxylase decreases the response to substance of Fluorouracil.	[15]
Paclitaxel	DMLB81S	Approved	Uroporphyrinogen decarboxylase decreases the response to substance of Paclitaxel.	[15]
Cyclophosphamide	DM4O2Z7	Approved	Uroporphyrinogen decarboxylase increases the Porphyrin metabolism disorder ADR of Cyclophosphamide.	[16]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Magnesium	DMU4ORS	Approved	Uroporphyrinogen decarboxylase affects the abundance of Magnesium.	[17]

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 Uroporphyrinogen decarboxylase.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Uroporphyrinogen decarboxylase.	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Uroporphyrinogen decarboxylase.	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Uroporphyrinogen decarboxylase.	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Uroporphyrinogen decarboxylase.	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the activity of Uroporphyrinogen decarboxylase.	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Uroporphyrinogen decarboxylase.	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Uroporphyrinogen decarboxylase.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Uroporphyrinogen decarboxylase.	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Uroporphyrinogen decarboxylase.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Uroporphyrinogen decarboxylase.	[13]

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] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Hepatoerythropoietic Porphyria. 2013 Oct 31 [updated 2022 Dec 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] 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.
• [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] 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.
• [8] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [9] High-dose vitamin E lowers urine porphyrin levels in patients affected by porphyria cutanea tarda. Pharmacol Res. 2002 Apr;45(4):355-9. doi: 10.1006/phrs.2002.0956.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [13] 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.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [15] Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer. Sci Transl Med. 2011 Jan 26;3(67):67ra7. doi: 10.1126/scitranslmed.3001922.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [17] Major and trace elements in whole blood of phlebotomized patients with porphyria cutanea tarda. J Trace Elem Med Biol. 2005;19(2-3):217-20. doi: 10.1016/j.jtemb.2005.07.011. Epub 2005 Oct 24.