Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXV0ZD0)

• DOT Name: Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2)
• Synonyms: PHS 2; EC 4.2.1.96; 4-alpha-hydroxy-tetrahydropterin dehydratase 2; DcoH-like protein DCoHm; Dimerization cofactor of hepatocyte nuclear factor 1 from muscle; HNF-1-alpha dimerization cofactor
• Gene Name: PCBD2
• Related Disease:
  Spondyloarthropathy
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Brain neoplasm
  Neoplasm
• UniProt ID: PHS2_HUMAN
• PDB ID: 4C45
• EC Number: 4.2.1.96
• Pfam ID: PF01329
• Sequence:
  MAAVLGALGATRRLLAALRGQSLGLAAMSSGTHRLTAEERNQAILDLKAAGWSELSERDA
  IYKEFSFHNFNQAFGFMSRVALQAEKMNHHPEWFNVYNKVQITLTSHDCGELTKKDVKLA
  KFIEKAAASV
• Function: Involved in tetrahydrobiopterin biosynthesis. Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2; Regulates the dimerization of homeodomain protein HNF-1-alpha and enhances its transcriptional activity.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS13433-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondyloarthropathy	DISBPYCZ	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[3]
Brain neoplasm	DISY3EKS	Limited	Altered Expression	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2) affects the response to substance of NAPQI.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[10]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Pterin-4-alpha-carbinolamine dehydratase 2 (PCBD2).	[14]

References

• [1] Autoantibodies to the HLA-B27 sequence cross-react with the hypothetical peptide from the arthritis-associated Shigella plasmid.J Clin Invest. 1990 Oct;86(4):1193-203. doi: 10.1172/JCI114825.
• [2] Expression of prostaglandin H synthase-2 in human brain tumors.Acta Neuropathol. 2001 Aug;102(2):181-7. doi: 10.1007/s004010100373.
• [3] Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect.Proc Natl Acad Sci U S A. 1996 May 14;93(10):4816-20. doi: 10.1073/pnas.93.10.4816.
• [4] Second generation sequencing of the mesothelioma tumor genome.PLoS One. 2010 May 13;5(5):e10612. doi: 10.1371/journal.pone.0010612.
• [5] 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.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] 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.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] 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.
• [15] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.