Target Information

Target General Information

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Target ID

T98397 (Former ID: TTDI00964)

Target Name

Thymidylate synthase (TYMS)

Synonyms

TSase; TS

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Gene Name

TYMS

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Stomach cancer [ICD-11: 2B72]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.

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BioChemical Class

Methyltransferase

UniProt ID

TYSY_HUMAN

EC Number

EC 2.1.1.45

Sequence

MPVAGSELPRRPLPPAAQERDAEPRPPHGELQYLGQIQHILRCGVRKDDRTGTGTLSVFG
MQARYSLRDEFPLLTTKRVFWKGVLEELLWFIKGSTNAKELSSKGVKIWDANGSRDFLDS
LGFSTREEGDLGPVYGFQWRHFGAEYRDMESDYSGQGVDQLQRVIDTIKTNPDDRRIIMC
AWNPRDLPLMALPPCHALCQFYVVNSELSCQLYQRSGDMGLGVPFNIASYALLTYMIAHI
TGLKPGDFIHTLGDAHIYLNHIEPLKIQLQREPRPFPKLRILRKVEKIDDFKAEDFQIEG
YNPHPTIKMEMAV

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Plevitrexed (R)-isomer

Drug Info

Phase 2

Gastric adenocarcinoma

[2]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

Plevitrexed (R)-isomer

Drug Info

[4]

Modulator

[+] 1 Modulator drugs

ICI-198583

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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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

[5]

PDB Sequence

PPHGELQYLG

³⁵

QIQHILRCGV

⁴⁵

RKDDRTGTGT

⁵⁵

LSVFGMQARY

⁶⁵

SLRDEFPLLT

⁷⁵

TKRVFWKGVL

⁸⁵

EELLWFIKGS

⁹⁵

TNAKELSSKG

¹⁰⁵

VKIWDANGSR

¹¹⁵

DFLDSLGFST

¹²⁵

REEGDLGPVY

¹³⁵

GFQWRHFGAE

¹⁴⁵

YRDMESDYSG

¹⁵⁵

QGVDQLQKVI

¹⁶⁵

DTIKTNPDDR

¹⁷⁵

RIIMCAWNPR

¹⁸⁵

DLPLMALPPC

¹⁹⁵

HALCQFYVVN

²⁰⁵

SELSCQLYQR

²¹⁵

SGDMGLGVPF

²²⁵

NIASYALLTY

²³⁵

MIAHITGLKP

²⁴⁵

GDFIHTLGDA

²⁵⁵

HIYLNHIEPL

²⁶⁵

KIQLQREPRP

²⁷⁵

FPKLRILRKV

²⁸⁵

EKIDDFKAED

²⁹⁵

FQIEGYNPHP

³⁰⁵

Residue

Distance (Å)

ARG50

3.163

GLU87

4.442

CYS195

3.557

HIS196

3.146

GLN214

4.983

ARG215

2.674

SER216

3.460

Residue

Distance (Å)

GLY217

3.836

ASP218

3.381

LEU221

4.077

GLY222

3.512

PHE225

3.562

ASN226

2.593

HIS256

4.496

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

[6]

PDB Sequence

HGELQYLGQI

³⁷

QHILRCGVEK

⁴⁷

DDRTGTGTLS

⁵⁷

VFGMQARYSL

⁶⁷

RDEFPLLTTK

⁷⁷

RVFWKGVLEE

⁸⁷

LLWFIKGSTN

⁹⁷

AKELSSKGVK

¹⁰⁷

IWDANGSRDF

¹¹⁷

LDSLGFSTRE

¹²⁷

EGDLGPVYGF

¹³⁷

QWRHFGAEYR

¹⁴⁷

DMESDYSGQG

¹⁵⁷

VDQLQRVIDT

¹⁶⁷

IKTNPDDRRI

¹⁷⁷

IMCAWNPRDL

¹⁸⁷

PLMALPPCHA

¹⁹⁷

LCQFYVVNSE

²⁰⁷

LSCQLYQRSG

²¹⁷

DMGLGVPFNI

²²⁷

ASYALLTYMI

²³⁷

AHITGLKPGD

²⁴⁷

FIHTLGDAHI

²⁵⁷

YLNHIEPLKI

²⁶⁷

QLQREPRPFP

²⁷⁷

KLRILRKVEK

²⁸⁷

IDDFKAEDFQ

²⁹⁷

IEGYNPHPTI

³⁰⁷

KMEMAV

Residue

Distance (Å)

LYS77

4.096

PHE80

3.210

GLU87

4.105

LYS107

4.886

ILE108

3.777

TRP109

3.627

ASN112

2.878

LEU192

4.521

ASP218

3.518

Residue

Distance (Å)

LEU221

3.757

GLY222

3.472

PHE225

3.640

TYR258

3.846

ILE307

3.937

MET309

4.962

MET311

3.571

ALA312

2.747

VAL313

4.953

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Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

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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

There is no similarity protein (E value < 0.005) for this target

KEGG Pathway	Pathway ID	Affiliated Target
Pyrimidine metabolism	hsa00240	Affiliated Target
Class: Metabolism => Nucleotide metabolism	Pathway Hierarchy
One carbon pool by folate	hsa00670	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy

Degree	25	Degree centrality	2.69E-03	Betweenness centrality	3.99E-03
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

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

References

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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

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 6

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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