Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOZ6NSL)

• DOT Name: GTP cyclohydrolase 1 (GCH1)
• Synonyms: EC 3.5.4.16; GTP cyclohydrolase I; GTP-CH-I
• Gene Name: GCH1
• Related Disease:
  Dystonia 5
  GTP cyclohydrolase I deficiency
  GTP cyclohydrolase I deficiency with hyperphenylalaninemia
• UniProt ID: GCH1_HUMAN
• PDB ID: 1FB1; 6Z80; 6Z85; 6Z86; 6Z87; 6Z88; 6Z89; 7ALA; 7ALB; 7ALC; 7ALQ
• EC Number: 3.5.4.16
• Pfam ID: PF01227
• Sequence:
  MEKGPVRAPAEKPRGARCSNGFPERDPPRPGPSRPAEKPPRPEAKSAQPADGWKGERPRS
  EEDNELNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDA
  IFDEDHDEMVIVKDIDMFSMCEHHLVPFVGKVHIGYLPNKQVLGLSKLARIVEIYSRRLQ
  VQERLTKQIAVAITEALRPAGVGVVVEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKT
  REEFLTLIRS
• Function: Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.
• Tissue Specificity: In epidermis, expressed predominantly in basal undifferentiated keratinocytes and in some but not all melanocytes (at protein level).
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
• BioCyc Pathway: MetaCyc:HS05586-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
Dystonia 5	DISMPJ7S	Definitive	Autosomal dominant	[1]
GTP cyclohydrolase I deficiency	DISFIL4X	Definitive	Semidominant	[2]
GTP cyclohydrolase I deficiency with hyperphenylalaninemia	DIS2N2VS	Definitive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	GTP cyclohydrolase 1 (GCH1) affects the response to substance of Topotecan.	[23]
Mitoxantrone	DMM39BF	Approved	GTP cyclohydrolase 1 (GCH1) affects the response to substance of Mitoxantrone.	[23]
Capsaicin	DMGMF6V	Approved	GTP cyclohydrolase 1 (GCH1) affects the response to substance of Capsaicin.	[24]

21 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 GTP cyclohydrolase 1 (GCH1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GTP cyclohydrolase 1 (GCH1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of GTP cyclohydrolase 1 (GCH1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GTP cyclohydrolase 1 (GCH1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP cyclohydrolase 1 (GCH1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of GTP cyclohydrolase 1 (GCH1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of GTP cyclohydrolase 1 (GCH1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of GTP cyclohydrolase 1 (GCH1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of GTP cyclohydrolase 1 (GCH1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of GTP cyclohydrolase 1 (GCH1).	[14]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of GTP cyclohydrolase 1 (GCH1).	[15]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of GTP cyclohydrolase 1 (GCH1).	[9]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of GTP cyclohydrolase 1 (GCH1).	[9]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of GTP cyclohydrolase 1 (GCH1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of GTP cyclohydrolase 1 (GCH1).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of GTP cyclohydrolase 1 (GCH1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of GTP cyclohydrolase 1 (GCH1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of GTP cyclohydrolase 1 (GCH1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GTP cyclohydrolase 1 (GCH1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of GTP cyclohydrolase 1 (GCH1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of GTP cyclohydrolase 1 (GCH1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GTP cyclohydrolase 1 (GCH1).	[11]

References

• [1] A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form. Neuroreport. 1999 Feb 25;10(3):487-91. doi: 10.1097/00001756-199902250-00008.
• [2] 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.
• [3] Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency. Neurology. 2003 Jan 28;60(2):335-7. doi: 10.1212/01.wnl.0000044049.99690.ad.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [14] The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-186.
• [15] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther. 2010 Oct;335(1):149-54.
• [18] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [19] 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.
• [20] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [24] Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain. 2009 Jan;141(1-2):114-8. doi: 10.1016/j.pain.2008.10.023. Epub 2008 Dec 9.