Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2PDQUJ)

• DOT Name: Uroporphyrinogen-III synthase
• Synonyms: UROIIIS; UROS; EC 4.2.1.75; Hydroxymethylbilane hydrolyase ; Uroporphyrinogen-III cosynthase
• Gene Name: UROS
• Related Disease: Cutaneous porphyria
• UniProt ID: HEM4_HUMAN
• PDB ID: 1JR2
• EC Number: 4.2.1.75
• Pfam ID: PF02602
• Sequence:
  MKVLLLKDAKEDDCGQDPYIRELGLYGLEATLIPVLSFEFLSLPSFSEKLSHPEDYGGLI
  FTSPRAVEAAELCLEQNNKTEVWERSLKEKWNAKSVYVVGNATASLVSKIGLDTEGETCG
  NAEKLAEYICSRESSALPLLFPCGNLKREILPKALKDKGIAMESITVYQTVAHPGIQGNL
  NSYYSQQGVPASITFFSPSGLTYSLKHIQELSGDNIDQIKFAAIGPTTARALAAQGLPVS
  CTAESPTPQALATGIRKALQPHGCC
• Function: Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins. Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme).
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS07569-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
Cutaneous porphyria	DISUQTL2	Definitive	Autosomal recessive	[1]

1 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 Uroporphyrinogen-III synthase.	[2]

8 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 Uroporphyrinogen-III synthase.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Uroporphyrinogen-III synthase.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Uroporphyrinogen-III synthase.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Uroporphyrinogen-III synthase.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Uroporphyrinogen-III synthase.	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Uroporphyrinogen-III synthase.	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Uroporphyrinogen-III synthase.	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Uroporphyrinogen-III synthase.	[9]

References

• [1] Heterogeneity of mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Hum Genet. 1992 Jan;88(3):320-4. doi: 10.1007/BF00197267.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [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.