Target Information
| Target General Information | Top | |||||
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| Target ID |
T98397
(Former ID: TTDI00964)
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| Target Name |
Thymidylate synthase (TYMS)
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| Synonyms |
TSase; TS
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| Gene Name |
TYMS
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Stomach cancer [ICD-11: 2B72] | |||||
| 2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.45
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| Sequence |
MPVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFG
MQARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDS LGFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMC AWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHI TGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEG YNPHPTIKMEMAV 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 | Plevitrexed (R)-isomer | Drug Info | Phase 2 | Gastric adenocarcinoma | [2] | |
| 2 | NUC-3373 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | Plevitrexed (R)-isomer | Drug Info | [4] | |||
| 2 | NUC-3373 | Drug Info | [5] | |||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ICI-198583 | 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: Glutathione | Ligand Info | |||||
| Structure Description | Human Thymidylate Synthase R163K with Cys 195 covalently modified by Glutathione | PDB:3OB7 | ||||
| Method | X-ray diffraction | Resolution | 2.75 Å | Mutation | Yes | [6] |
| PDB Sequence |
PPHGELQYLG
35 QIQHILRCGV45 RKDDRTGTGT55 LSVFGMQARY65 SLRDEFPLLT75 TKRVFWKGVL 85 EELLWFIKGS95 TNAKELSSKG105 VKIWDANGSR115 DFLDSLGFST125 REEGDLGPVY 135 GFQWRHFGAE145 YRDMESDYSG155 QGVDQLQKVI165 DTIKTNPDDR175 RIIMCAWNPR 185 DLPLMALPPC195 HALCQFYVVN205 SELSCQLYQR215 SGDMGLGVPF225 NIASYALLTY 235 MIAHITGLKP245 GDFIHTLGDA255 HIYLNHIEPL265 KIQLQREPRP275 FPKLRILRKV 285 EKIDDFKAED295 FQIEGYNPHP305 T
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| Ligand Name: Pemetrexed | Ligand Info | |||||
| Structure Description | Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate | PDB:1JU6 | ||||
| Method | X-ray diffraction | Resolution | 2.89 Å | Mutation | Yes | [7] |
| PDB Sequence |
HGELQYLGQI
37 QHILRCGVEK47 DDRTGTGTLS57 VFGMQARYSL67 RDEFPLLTTK77 RVFWKGVLEE 87 LLWFIKGSTN97 AKELSSKGVK107 IWDANGSRDF117 LDSLGFSTRE127 EGDLGPVYGF 137 QWRHFGAEYR147 DMESDYSGQG157 VDQLQRVIDT167 IKTNPDDRRI177 IMCAWNPRDL 187 PLMALPPCHA197 LCQFYVVNSE207 LSCQLYQRSG217 DMGLGVPFNI227 ASYALLTYMI 237 AHITGLKPGD247 FIHTLGDAHI257 YLNHIEPLKI267 QLQREPRPFP277 KLRILRKVEK 287 IDDFKAEDFQ297 IEGYNPHPTI307 KMEMAV
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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 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 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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Pyrimidine metabolism | hsa00240 | Affiliated Target |
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| Class: Metabolism => Nucleotide metabolism | Pathway Hierarchy | ||
| One carbon pool by folate | hsa00670 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 25 | Degree centrality | 2.69E-03 | Betweenness centrality | 3.99E-03 |
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| Closeness centrality | 2.18E-01 | Radiality | 1.38E+01 | Clustering coefficient | 2.30E-01 |
| Neighborhood connectivity | 2.87E+01 | Topological coefficient | 9.74E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| References | Top | |||||
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| REF 1 | The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583). Biochem Pharmacol. 1991 Oct 24;42(10):1885-95. | |||||
| REF 2 | Clinical pipeline report, company report or official report of plevitrexed. | |||||
| REF 3 | ClinicalTrials.gov (NCT02723240) NUC-3373 in Advanced Solid Tumours (NuTide:301). U.S. National Institutes of Health. | |||||
| REF 4 | Differential effect of 1,10-phenanthroline on mammalian, yeast, and parasite glycosylphosphatidylinositol anchor synthesis. Biochem Biophys Res Commun. 2001 Nov 16;288(5):1112-8. | |||||
| REF 5 | Clinical pipeline report, company report or official report of NuCana. | |||||
| REF 6 | Structures of human thymidylate synthase R163K with dUMP, FdUMP and glutathione show asymmetric ligand binding. Acta Crystallogr D Biol Crystallogr. 2011 Jan;67(Pt 1):60-6. | |||||
| REF 7 | Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases. J Mol Biol. 2001 Nov 2;313(4):813-29. | |||||
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