Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3P47DC)

• DOT Name: Porphobilinogen deaminase (HMBS)
• Synonyms: PBG-D; EC 2.5.1.61; Hydroxymethylbilane synthase; HMBS; Pre-uroporphyrinogen synthase
• Gene Name: HMBS
• Related Disease: Acute intermittent hepatic porphyria
• UniProt ID: HEM3_HUMAN
• PDB ID: 3ECR; 3EQ1; 5M6R; 5M7F; 7AAJ; 7AAK; 7CCX; 7CCY; 7CCZ; 7CD0; 8PND
• EC Number: 2.5.1.61
• Pfam ID: PF01379 ; PF03900
• Sequence:
  MSGNGNAAATAEENSPKMRVIRVGTRKSQLARIQTDSVVATLKASYPGLQFEIIAMSTTG
  DKILDTALSKIGEKSLFTKELEHALEKNEVDLVVHSLKDLPTVLPPGFTIGAICKRENPH
  DAVVFHPKFVGKTLETLPEKSVVGTSSLRRAAQLQRKFPHLEFRSIRGNLNTRLRKLDEQ
  QEFSAIILATAGLQRMGWHNRVGQILHPEECMYAVGQGALGVEVRAKDQDILDLVGVLHD
  PETLLRCIAERAFLRHLEGGCSVPVAVHTAMKDGQLYLTGGVWSLDGSDSIQETMQATIH
  VPAQHEDGPEDDPQLVGITARNIPRGPQLAAQNLGISLANLLLSKGAKNILDVARQLNDA
  H
• Function: As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen. Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assembled. In the last step of catalysis, the product, preuroporphyrinogen, is released, leaving the cofactor bound to the holodeaminase intact.
• Tissue Specificity: .Is ubiquitously expressed.; [Isoform 2]: Is found only in erythroid cells.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS07607-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
Acute intermittent hepatic porphyria	DIS80J7E	Definitive	Semidominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloroquine	DMSI5CB	Phase 3 Trial	Porphobilinogen deaminase (HMBS) increases the response to substance of Chloroquine.	[20]

17 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 Porphobilinogen deaminase (HMBS).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Porphobilinogen deaminase (HMBS).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Porphobilinogen deaminase (HMBS).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Porphobilinogen deaminase (HMBS).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Porphobilinogen deaminase (HMBS).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Porphobilinogen deaminase (HMBS).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine decreases the activity of Porphobilinogen deaminase (HMBS).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Porphobilinogen deaminase (HMBS).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Porphobilinogen deaminase (HMBS).	[10]
Aclarubicin	DMLFZHD	Approved	Aclarubicin increases the expression of Porphobilinogen deaminase (HMBS).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Porphobilinogen deaminase (HMBS).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Porphobilinogen deaminase (HMBS).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Porphobilinogen deaminase (HMBS).	[15]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Porphobilinogen deaminase (HMBS).	[16]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Porphobilinogen deaminase (HMBS).	[11]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of Porphobilinogen deaminase (HMBS).	[17]
Chebulinic acid	DMR8HKC	Investigative	Chebulinic acid decreases the expression of Porphobilinogen deaminase (HMBS).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenol	DM1QSM3	Phase 2/3	Phenol increases the methylation of Porphobilinogen deaminase (HMBS).	[13]
Catechol	DML0YEK	Investigative	Catechol increases the methylation of Porphobilinogen deaminase (HMBS).	[18]

References

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• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Carbamazepine-induced non-hereditary acute porphyria. Lancet. 1983 Apr 9;1(8328):790-2. doi: 10.1016/s0140-6736(83)91850-0.
• [9] 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.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] Oxidative stress involvement in chemically induced differentiation of K562 cells. Free Radic Biol Med. 2000 Jan 1;28(1):18-27.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to phenol and hydroquinone. Toxicology. 2013 Oct 4;312:108-14. doi: 10.1016/j.tox.2013.08.007. Epub 2013 Aug 20.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [17] Phenolic metabolites of benzene inhibited the erythroid differentiation of K562 cells. Toxicol Lett. 2011 Jun 24;203(3):190-9. doi: 10.1016/j.toxlet.2011.03.012. Epub 2011 Mar 23.
• [18] Changes in DNA methylation of erythroid-specific genes in K562 cells exposed to catechol in long term. Toxicol In Vitro. 2017 Sep;43:21-28. doi: 10.1016/j.tiv.2017.05.019. Epub 2017 May 25.
• [19] Effects of chebulinic acid on differentiation of human leukemia K562 cells. Acta Pharmacol Sin. 2004 Feb;25(2):231-8.
• [20] Precipitation of acute intermittent porphyria by chloroquin. Indian Pediatr. 1996 Mar;33(3):241-3.