Target Information
| Target General Information | Top | |||||
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| Target ID |
T26900
(Former ID: TTDI03226)
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| Target Name |
Glutamic acid decarboxylase 1 (GAD1)
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| Synonyms |
Glutamate decarboxylase 67 kDa isoform; Glutamate decarboxylase 1; GAD67; GAD-67; GAD; 67 kDa glutamic acid decarboxylase
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| Gene Name |
GAD1
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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 |
Catalyzes the production of GABA.
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| UniProt ID | ||||||
| EC Number |
EC 4.1.1.15
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| Sequence |
MASSTPSSSATSSNAGADPNTTNLRPTTYDTWCGVAHGCTRKLGLKICGFLQRTNSLEEK
SRLVSAFKERQSSKNLLSCENSDRDARFRRTETDFSNLFARDLLPAKNGEEQTVQFLLEV VDILLNYVRKTFDRSTKVLDFHHPHQLLEGMEGFNLELSDHPESLEQILVDCRDTLKYGV RTGHPRFFNQLSTGLDIIGLAGEWLTSTANTNMFTYEIAPVFVLMEQITLKKMREIVGWS SKDGDGIFSPGGAISNMYSIMAARYKYFPEVKTKGMAAVPKLVLFTSEQSHYSIKKAGAA LGFGTDNVILIKCNERGKIIPADFEAKILEAKQKGYVPFYVNATAGTTVYGAFDPIQEIA DICEKYNLWLHVDAAWGGGLLMSRKHRHKLNGIERANSVTWNPHKMMGVLLQCSAILVKE KGILQGCNQMCAGYLFQPDKQYDVSYDTGDKAIQCGRHVDIFKFWLMWKAKGTVGFENQI NKCLELAEYLYAKIKNREEFEMVFNGEPEHTNVCFWYIPQSLRGVPDSPQRREKLHKVAP KIKALMMESGTTMVGYQPQGDKANFFRMVISNPAATQSDIDFLIEEIERLGQDL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T64V6C | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | AAV-GAD | Drug Info | Phase 2 | Parkinson disease | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | s-allylglycine | Drug Info | [1] | |||
| 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: Chelidonic acid | Ligand Info | |||||
| Structure Description | Structural characterization of Glutamic Acid Decarboxylase; insights into the mechanism of autoinactivation | PDB:3VP6 | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [4] |
| PDB Sequence |
TDFSNLFARD
102 LLPAKNGEEQ112 TVQFLLEVVD122 ILLNYVRKTF132 DRSTKVLDFH142 HPHQLLEGME 152 GFNLELSDHP162 ESLEQILVDC172 RDTLKYGVRT182 GHPRFFNQLS192 TGLDIIGLAG 202 EWLTSTANTN212 MFTYEIAPVF222 VLMEQITLKK232 MREIVGWSSK242 DGDGIFSPGG 252 AISNMYSIMA262 ARYKYFPEVK272 TKGMAAVPKL282 VLFTSEQSHY292 SIKKAGAALG 302 FGTDNVILIK312 CNERGKIIPA322 DFEAKILEAK332 QKGYVPFYVN342 ATAGTTVYGA 352 FDPIQEIADI362 CEKYNLWLHV372 DAAWGGGLLM382 SRKHRHKLNG392 IERANSVTWN 402 PHMMGVLLQC413 SAILVKEKGI423 LQGCNQMHAS433 YLFQQDKHYD443 VSYDTGDKAI 453 QCGRHVDIFK463 FWLMWKAKGT473 VGFENQINKC483 LELAEYLYAK493 IKNREEFEMV 503 FNGEPEHTNV513 CFWYIPQSLR523 GVPDSPQRRE533 KLHKVAPKIK543 ALMMESGTTM 553 VGYQPQGDKA563 NFFRMVISNP573 AATQSDIDFL583 IEEIERLGQ
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| Ligand Name: N6-((3-Hydroxy-2-methyl-5-((phosphonooxy)methyl)-4-pyridinyl)methylene)-L-lysine | Ligand Info | |||||
| Structure Description | Structural characterization of Glutamic Acid Decarboxylase; insights into the mechanism of autoinactivation | PDB:3VP6 | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [4] |
| PDB Sequence |
TDFSNLFARD
102 LLPAKNGEEQ112 TVQFLLEVVD122 ILLNYVRKTF132 DRSTKVLDFH142 HPHQLLEGME 152 GFNLELSDHP162 ESLEQILVDC172 RDTLKYGVRT182 GHPRFFNQLS192 TGLDIIGLAG 202 EWLTSTANTN212 MFTYEIAPVF222 VLMEQITLKK232 MREIVGWSSK242 DGDGIFSPGG 252 AISNMYSIMA262 ARYKYFPEVK272 TKGMAAVPKL282 VLFTSEQSHY292 SIKKAGAALG 302 FGTDNVILIK312 CNERGKIIPA322 DFEAKILEAK332 QKGYVPFYVN342 ATAGTTVYGA 352 FDPIQEIADI362 CEKYNLWLHV372 DAAWGGGLLM382 SRKHRHKLNG392 IERANSVTWN 402 PHMMGVLLQC413 SAILVKEKGI423 LQGCNQMHAS433 YLFQQDKHYD443 VSYDTGDKAI 453 QCGRHVDIFK463 FWLMWKAKGT473 VGFENQINKC483 LELAEYLYAK493 IKNREEFEMV 503 FNGEPEHTNV513 CFWYIPQSLR523 GVPDSPQRRE533 KLHKVAPKIK543 ALMMESGTTM 553 VGYQPQGDKA563 NFFRMVISNP573 AATQSDIDFL583 IEEIERLGQ
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LEU191
3.343
SER192
3.347
GLY251
3.162
GLY252
2.648
ALA253
2.875
ASN256
3.782
HIS291
3.292
SER293
4.138
THR344
4.127
GLY346
3.600
THR347
4.812
THR348
3.118
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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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| Alanine, aspartate and glutamate metabolism | hsa00250 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| beta-Alanine metabolism | hsa00410 | Affiliated Target |
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| Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
| Taurine and hypotaurine metabolism | hsa00430 | Affiliated Target |
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| Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
| Butanoate metabolism | hsa00650 | Affiliated Target |
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| Class: Metabolism => Carbohydrate metabolism | Pathway Hierarchy | ||
| GABAergic synapse | hsa04727 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 4.53E-04 |
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| Closeness centrality | 1.91E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.17E+01 | Topological coefficient | 3.44E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| References | Top | |||||
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| REF 1 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1272). | |||||
| REF 2 | ClinicalTrials.gov (NCT00643890) Phase 2 Safety and Efficacy Study Evaluating Glutamic Acid Decarboxylase Gene Transfer to Subthalamic Nuclei in Subjects With Advanced Parkinson's Disease. U.S.National Institutes of Health. | |||||
| REF 3 | Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet. 2007 Jun 23;369(9579):2097-105. | |||||
| REF 4 | Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates. Biosci Rep. 2013 Jan 11;33(1):137-44. | |||||
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