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Gene Review

thyA  -  thymidylate synthetase

Escherichia coli str. K-12 substr. MG1655

Synonyms: ECK2823, JW2795
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Disease relevance of thyA

  • This open reading frame is immediately 5' to the thyA gene and is allelic to umpA of Escherichia coli [1].
  • Bacillus subtilis strain 168 is known to possess two genes that encode thymidylate synthases, thyA and thyB [2].
  • Analysis of thyA genes cloned from B. subtilis W23 strain 2A6, B. subtilis ATCC6633, B. amyloliquefaciens S18 and B. atrophaeus S223 reveals that they are very similar to the thyA genes from B. subtilis 168 and its phage phi3T, but differ considerably from the majority of known prokaryotic and eukaryotic thymidylate synthases [2].
  • This method was applied to generate a potent inhibitor for thymidylate synthase, an essential enzyme in pyrimidine metabolism with therapeutic applications in cancer and infectious diseases [3].
  • However, the development of potent cofactor analog inhibitors of TS, such as CB3717, as drugs has been slowed by their toxicity, which often becomes apparent as hepatic and renal toxicity mediated by the specific chemistry of the compound [4].

High impact information on thyA

  • Inactivity of N229A thymidylate synthase due to water-mediated effects: isolating a late stage in methyl transfer [5].
  • Mutation of thymidylate synthase N229(177) to alanine results in an essentially inactive enzyme, yet it leads to formation of a stable ternary complex [5].
  • The enzyme thymidylate synthase (TS) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate (dUMP) to 2'-deoxythymidine 5'-monophosphate [6].
  • The role of protein dynamics in thymidylate synthase catalysis: variants of conserved 2'-deoxyuridine 5'-monophosphate (dUMP)-binding Tyr-261 [6].
  • The structure also provides insight into the role of specific waters in the active site which have been suggested to be important in the TS reaction [7].

Chemical compound and disease context of thyA

  • We have addressed the role of glutamate 60(58) in the TS reaction by cocrystalizing the Escherichia coli TS mutant E60(58)Q with dUMP and the cofactor analog CB3717 and have determined the X-ray crystal structure to 2.5 A resolution with a final R factor of 15.2% (Rfree = 24.0%) [7].
  • The structure of a polyglutamyl cofactor analog bound in ternary complex with deoxyuridine monophosphate (dUMP) and Escherichia coli TS reveals how the polyglutamyl moiety is positioned in TS and accounts in a qualitative way for the binding contributions of the different individual glutamate residues [8].
  • Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity [4].
  • Tyr94 of Escherichia coli thymidylate synthase is thought to be involved, either directly or by activation of a water molecule, in the abstraction of a proton from C5 of the 2'-deoxyuridine 5'-monophosphate (dUMP) substrate [9].

Biological context of thyA


Associations of thyA with chemical compounds


Regulatory relationships of thyA


Analytical, diagnostic and therapeutic context of thyA


  1. Isolation and characterization of a temperature-sensitive mutant of Salmonella typhimurium defective in prolipoprotein modification. Gan, K., Gupta, S.D., Sankaran, K., Schmid, M.B., Wu, H.C. J. Biol. Chem. (1993) [Pubmed]
  2. Genes encoding thymidylate synthases A and B in the genus Bacillus are members of two distinct families. Tam, N.H., Borriss, R. Mol. Gen. Genet. (1998) [Pubmed]
  3. Site-directed ligand discovery. Erlanson, D.A., Braisted, A.C., Raphael, D.R., Randal, M., Stroud, R.M., Gordon, E.M., Wells, J.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Binding of the anticancer drug ZD1694 to E. coli thymidylate synthase: assessing specificity and affinity. Rutenber, E.E., Stroud, R.M. Structure (1996) [Pubmed]
  5. Inactivity of N229A thymidylate synthase due to water-mediated effects: isolating a late stage in methyl transfer. Reyes, C.L., Sage, C.R., Rutenber, E.E., Nissen, R.M., Finer-Moore, J.S., Stroud, R.M. J. Mol. Biol. (1998) [Pubmed]
  6. The role of protein dynamics in thymidylate synthase catalysis: variants of conserved 2'-deoxyuridine 5'-monophosphate (dUMP)-binding Tyr-261. Newby, Z., Lee, T.T., Morse, R.J., Liu, Y., Liu, L., Venkatraman, P., Santi, D.V., Finer-Moore, J.S., Stroud, R.M. Biochemistry (2006) [Pubmed]
  7. An essential role for water in an enzyme reaction mechanism: the crystal structure of the thymidylate synthase mutant E58Q. Sage, C.R., Rutenber, E.E., Stout, T.J., Stroud, R.M. Biochemistry (1996) [Pubmed]
  8. Structural basis for recognition of polyglutamyl folates by thymidylate synthase. Kamb, A., Finer-Moore, J., Calvert, A.H., Stroud, R.M. Biochemistry (1992) [Pubmed]
  9. Structure of the Y94F mutant of Escherichia coli thymidylate synthase. Roberts, S.A., Hyatt, D.C., Honts, J.E., Changchien, L., Maley, G.F., Maley, F., Montfort, W.R. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2006) [Pubmed]
  10. Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate. Montfort, W.R., Perry, K.M., Fauman, E.B., Finer-Moore, J.S., Maley, G.F., Hardy, L., Maley, F., Stroud, R.M. Biochemistry (1990) [Pubmed]
  11. Crystal structure of thymidylate synthase A from Bacillus subtilis. Fox, K.M., Maley, F., Garibian, A., Changchien, L.M., Van Roey, P. Protein Sci. (1999) [Pubmed]
  12. Amino acid substitution analysis of E. coli thymidylate synthase: the study of a highly conserved region at the N-terminus. Kim, C.W., Michaels, M.L., Miller, J.H. Proteins (1992) [Pubmed]
  13. Nucleotide sequence of the thymidylate synthase B and dihydrofolate reductase genes contained in one Bacillus subtilis operon. Iwakura, M., Kawata, M., Tsuda, K., Tanaka, T. Gene (1988) [Pubmed]
  14. Water-mediated substrate/product discrimination: the product complex of thymidylate synthase at 1.83 A. Fauman, E.B., Rutenber, E.E., Maley, G.F., Maley, F., Stroud, R.M. Biochemistry (1994) [Pubmed]
  15. The umpA gene of Escherichia coli encodes phosphatidylglycerol:prolipoprotein diacylglyceryl transferase (lgt) and regulates thymidylate synthase levels through translational coupling. Gan, K., Sankaran, K., Williams, M.G., Aldea, M., Rudd, K.E., Kushner, S.R., Wu, H.C. J. Bacteriol. (1995) [Pubmed]
  16. Pre-replication assembly of E. coli replisome components. den Blaauwen, T., Aarsman, M.E., Wheeler, L.J., Nanninga, N. Mol. Microbiol. (2006) [Pubmed]
  17. Sequence analysis and functional study of thymidylate synthase from zebrafish, Danio rerio. Du, C., Niu, R., Chu, E., Zhang, P., Lin, X. J. Biochem. (2006) [Pubmed]
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