Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAIY2T8)

• DOT Name: Beta-ureidopropionase
• Synonyms: EC 3.5.1.6; BUP-1; Beta-alanine synthase; N-carbamoyl-beta-alanine amidohydrolase
• Gene Name: UPB1
• Related Disease: Beta-ureidopropionase deficiency
• UniProt ID: BUP1_HUMAN
• PDB ID: 6FTQ
• EC Number: 3.5.1.6
• Pfam ID: PF00795
• Sequence:
  MAGAEWKSLEECLEKHLPLPDLQEVKRVLYGKELRKLDLPREAFEAASREDFELQGYAFE
  AAEEQLRRPRIVHVGLVQNRIPLPANAPVAEQVSALHRRIKAIVEVAAMCGVNIICFQEA
  WTMPFAFCTREKLPWTEFAESAEDGPTTRFCQKLAKNHDMVVVSPILERDSEHGDVLWNT
  AVVISNSGAVLGKTRKNHIPRVGDFNESTYYMEGNLGHPVFQTQFGRIAVNICYGRHHPL
  NWLMYSINGAEIIFNPSATIGALSESLWPIEARNAAIANHCFTCAINRVGTEHFPNEFTS
  GDGKKAHQDFGYFYGSSYVAAPDSSRTPGLSRSRDGLLVAKLDLNLCQQVNDVWNFKMTG
  RYEMYARELAEAVKSNYSPTIVKE
• Function: Catalyzes a late step in pyrimidine degradation. Converts N-carbamoyl-beta-alanine (3-ureidopropanoate) into beta-alanine, ammonia and carbon dioxide. Likewise, converts N-carbamoyl-beta-aminoisobutyrate (3-ureidoisobutyrate) into beta-aminoisobutyrate, ammonia and carbon dioxide (Probable).
• Tissue Specificity: Detected in liver (at protein level).
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  beta-Alanine metabolism (hsa00410)
  Pantothe.te and CoA biosynthesis (hsa00770)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)
• BioCyc Pathway: MetaCyc:HS01953-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
Beta-ureidopropionase deficiency	DISHB6I4	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
toxaphene	DM4R657	Investigative	Beta-ureidopropionase affects the response to substance of toxaphene.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Beta-ureidopropionase.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Beta-ureidopropionase.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-ureidopropionase.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-ureidopropionase.	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Beta-ureidopropionase.	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Beta-ureidopropionase.	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Beta-ureidopropionase.	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Beta-ureidopropionase.	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Beta-ureidopropionase.	[10]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Beta-ureidopropionase.	[11]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Beta-ureidopropionase.	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Beta-ureidopropionase.	[13]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Beta-ureidopropionase.	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Beta-ureidopropionase.	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Beta-ureidopropionase.	[15]

References

• [1] 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.
• [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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.