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thymidylate synthetase

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Target id: 2642

Nomenclature: thymidylate synthetase

Abbreviated Name: TYMS

Family: 2.1.1.- Methyltransferases, Nucleoside synthesis and metabolism

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 313 18p11.32 TYMS thymidylate synthetase
Mouse - 307 5 15.81 cM Tyms thymidylate synthase
Rat - 307 9q38 Tyms thymidylate synthetase
Previous and Unofficial Names Click here for help
TMS | Tsase
Database Links Click here for help
BRENDA
CATH/Gene3D
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of human thymidylate synthase bound to a peptide inhibitor
PDB Id:  3N5E
Resolution:  2.26Å
Species:  Human
References:  2
Enzyme Reaction Click here for help
EC Number: 2.1.1.45

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
plevitrexed Small molecule or natural product Mm Inhibition 9.4 pKi 6
pKi 9.4 (Ki 4.4x10-10 M) [6]
Description: Measured using partially purified thymidylate synthase from mouse L1210 leukemia cells.
ONX-0801 Small molecule or natural product Ligand has a PDB structure Mm Inhibition 8.9 pKi 5
pKi 8.9 (Ki 1.2x10-9 M) [5]
Description: Thymidylate synthase isolated from mouse L1210 lymphocytic leukemia cells.
pemetrexed Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.0 pKi 8
pKi 7.0 (Ki 1.09x10-7 M) [8]
raltitrexed Small molecule or natural product Approved drug Ligand has a PDB structure Mm Inhibition 6.4 pKi 1
pKi 6.4 (Ki 4.18x10-7 M) [1]
raltitrexed Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Inhibition 6.5 pIC50 4
pIC50 6.5 (IC50 2.9x10-7 M) [4]
capecitabine Small molecule or natural product Approved drug Primary target of this compound Hs Inhibition - - 3,7
[3,7]
View species-specific inhibitor tables
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0034097 response to cytokine IEA

References

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1. Bisset GM, Pawelczak K, Jackman AL, Calvert AH, Hughes LR. (1992) Syntheses and thymidylate synthase inhibitory activity of the poly-gamma-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino ]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates. J Med Chem, 35 (5): 859-66. [PMID:1372358]

2. Cardinale D, Guaitoli G, Tondi D, Luciani R, Henrich S, Salo-Ahen OM, Ferrari S, Marverti G, Guerrieri D, Ligabue A et al.. (2011) Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase. Proc Natl Acad Sci USA, 108 (34): E542-9. [PMID:21795601]

3. Carlini LE, Meropol NJ, Bever J, Andria ML, Hill T, Gold P, Rogatko A, Wang H, Blanchard RL. (2005) UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res, 11 (3): 1226-36. [PMID:15709193]

4. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL. (2012) Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg Med Chem, 20 (14): 4217-25. [PMID:22739090]

5. Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E et al.. (2005) BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors. Cancer Res, 65 (24): 11721-8. [PMID:16357184]

6. Marsham PR, Wardleworth JM, Boyle FT, Hennequin LF, Kimbell R, Brown M, Jackman AL. (1999) Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors. J Med Chem, 42 (19): 3809-20. [PMID:10508430]

7. Papamichael D. (1999) The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status. Oncologist, 4 (6): 478-87. [PMID:10631692]

8. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. (1998) Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul, 38: 135-52. [PMID:9762351]

How to cite this page

Nucleoside synthesis and metabolism: thymidylate synthetase. Last modified on 28/11/2018. Accessed on 24/06/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2642.