Target Information
| Target General Information | Top | |||||
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| Target ID |
T28226
(Former ID: TTDR00115)
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| Target Name |
GTP cyclohydrolase-I (GCH1)
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| Synonyms |
Guanosine triphosphate cyclohydrolase I; GTP-CH-I; GTP cyclohydrolase I; GTP cyclohydrolase 1; GCH; DYT5
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| Gene Name |
GCH1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Parkinsonism [ICD-11: 8A00] | |||||
| Function |
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. Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
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| BioChemical Class |
Carbon-nitrogen hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.5.4.16
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| Sequence |
MEKGPVRAPAEKPRGARCSNGFPERDPPRPGPSRPAEKPPRPEAKSAQPADGWKGERPRS
EEDNELNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDA IFDEDHDEMVIVKDIDMFSMCEHHLVPFVGKVHIGYLPNKQVLGLSKLARIVEIYSRRLQ VQERLTKQIAVAITEALRPAGVGVVVEATHMCMVMRGVQKMNSKTVTSTMLGVFREDPKT REEFLTLIRS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | OXB-102 | Drug Info | Phase 1/2 | Parkinson disease | [2] | |
| 2 | ProSavin | Drug Info | Phase 1/2 | Parkinson disease | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | Guanine | Drug Info | [1] | |||
| 2 | 2-Propanol, Isopropanol | Drug Info | [6] | |||
| 3 | 8-hydroxyguanine | Drug Info | [1] | |||
| 4 | Guanosine-5'-Triphosphate | Drug Info | [7] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ProSavin | Drug Info | [5] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: L-phenylalanine | Ligand Info | |||||
| Structure Description | human GCH-GFRP stimulatory complex | PDB:7ALC | ||||
| Method | X-ray diffraction | Resolution | 1.73 Å | Mutation | No | [8] |
| PDB Sequence |
PRSEEDNELN
67 LPNLAAAYSS77 ILSSLGENPQ87 RQGLLKTPWR97 AASAMQFFTK107 GYQETISDVL 117 NDAIFDEDHD127 EMVIVKDIDM137 FSMCEHHLVP147 FVGKVHIGYL157 PNKQVLGLSK 167 LARIVEIYSR177 RLQVQERLTK187 QIAVAITEAL197 RPAGVGVVVE207 ATHMCMNSKT 225 VTSTMLGVFR235 EDPKTREEFL245 TLIR
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| Ligand Name: 7,8-dihydrobiopterin | Ligand Info | |||||
| Structure Description | human GCH-GFRP inhibitory complex 7-deaza-GTP bound | PDB:7ALQ | ||||
| Method | X-ray diffraction | Resolution | 2.21 Å | Mutation | No | [9] |
| PDB Sequence |
PRSEEDNELN
67 LPNLAAAYSS77 ILSSLGENPQ87 RQGLLKTPWR97 AASAMQFFTK107 GYQETISDVL 117 NDAIFDEDHD127 EMVIVKDIDM137 FSMCEHHLVP147 FVGKVHIGYL157 PNKQVLGLSK 167 LARIVEIYSR177 RLQVQERLTK187 QIAVAITEAL197 RPAGVGVVVE207 ATHMCMVMRG 217 VQKMNSKTVT227 STMLGVFRED237 PKTREEFLTL247 IR
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Folate biosynthesis | hsa00790 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 2.13E-04 |
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| Closeness centrality | 1.48E-01 | Radiality | 1.19E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.00E+00 | Topological coefficient | 3.33E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-interacting Proteins | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Pterine Biosynthesis | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation | |||||
| References | Top | |||||
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| REF 1 | GTP cyclohydrolase I feedback regulatory protein-dependent and -independent inhibitors of GTP cyclohydrolase I. Arch Biochem Biophys. 2001 Apr 1;388(1):67-73. | |||||
| REF 2 | ClinicalTrials.gov (NCT03720418) Study of OXB-102 (AXO-Lenti-PD) in Patients With Bilateral, Idiopathic Parkinson's Disease (SUNRISE-PD). U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01856439) Long Term Safety and Efficacy Study of ProSavin in Parkinson's Disease. U.S. National Institutes of Health. | |||||
| REF 4 | Clinical pipeline report, company report or official report of Oxford BioMedica. | |||||
| REF 5 | Clinical pipeline report, company report or official report of Oxford BioMedica. | |||||
| REF 6 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 7 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 8 | A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I. Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31838-31849. | |||||
| REF 9 | Biophysical and structural investigation of the regulation of human GTP cyclohydrolase I by its regulatory protein GFRP. J Struct Biol. 2021 Mar;213(1):107691. | |||||
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