Thymidylate Synthesis

Roy Kisliuk, Tufts University School of Medicine, Boston, Massachusetts, USA

Published online: January 2006

DOI: 10.1038/npg.els.0003923

Thymidylate, an essential component of DNA, is synthesized from deoxyuridylate and methylenetetrahydrofolate by thymidylate synthase, but dihydrofolate reductase and serine hydroxymethyltransferase are required to regenerate methylenetetrahydrofolate. Inhibitors of the synthase and the reductase arrest cell replication and are used in the treatment of cancer.

Keywords: methylenetetrahydrofolate; deoxyuridylate; methotrexate; fluorouracil; Tomudex

Figure 1. Thymidylate synthesis and incorporation into DNA.
Figure 2. The chemical structure of 5,10-methylene-5,6,7,8,-tetrahydrofolic acid ( CH2H4PteGlu). (PteGlu=pteroylglutamic acid.)
Figure 3. The thymidylate cycle involving ThyA thymidylate synthase. (1) thymidylate synthase; (2) dihydrofolate reductase; (3) serine hydroxymethyltransferase; dRP=2’-deoxyribose-5’ phosphate. Structures in boxes represent portions of the participating folate coenzymes; tetrahydrofolate ( H4PteGlun), 5,10-methylenetetrahydrofolate ( CH2-H4PteGlun) and 7,8-dihydrofolate ( H2PteGlun). n=the number of glutamate residues.
Figure 4. Outline of thymidylate (dTMP) and thymidine metabolism in cytosol and mitochondria of human cells; TS=thymidylate synthase, TK=thymidine kinase, dNT – deoxyribonucleotidase, TP=thymidine phosphorylase, DPD=dihydropyrimidine dehydrogenase.
Figure 5. Degradation of thymidine and thymine arising from DNA breakdown, thymidylate and the diet.
Figure 6. Inhibitors of thymidylate synthesis.
Figure 7. Thymidylate synthase pathway utilizing the ThyX gene product. DRP=2’-deoxyribose-5’-phosphate.
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 References
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 Further Reading
    Carreras CW and Santi DV (1995) The catalytic mechanism and structure of thymidylate synthase. Annual Review of Biochemistry 64: 721–762.

Related Sub-Topics:

Other Biomolecules: Structure, Function, Metabolism | Nucleic Acids: Structure, Function, Metabolism
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Article Title: Thymidylate Synthesis
 
How to Cite close
Kisliuk, Roy(Jan 2006) Thymidylate Synthesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0003923]