Thymidylate Synthesis Chapter uri icon

abstract

  • Abstract Thymidylate is a component of DNA (deoxyribonucleic acid), and is synthesised from the de novo or nucleotide salvage pathways. Many cell types rely on the salvage pathway, but often this is insufficient. Thymidylate is synthesised de novo from deoxyuridylate and methylenetetrahydrofolate by thymidylate synthase (TYMS), with the enzymes dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase (SHMT) or methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) which are required to regenerate methylenetetrahydrofolate. The de novo synthesis pathway forms a nuclear complex at the nuclear lamina at sites of DNA replication. DNA polymerases do not distinguish between deoxyuridylate and thymidylate, and when thymidylate synthesis is insufficient, uracil is misincorporated into DNA. This can lead to futile cycles of DNA repair and subsequent DNA single and doublestrand breaks. Impaired de novo thymidylate synthesis can result in neural tube defects, megaloblastic anaemia and severe combined immunodeficiency (SCID). Inhibitors of TYMS and DHFR impair cell replication and have been used in the treatment of cancer. Key Concepts Thymidylate (deoxythymidine 5monophosphate, 5methyluracil2deoxyriboside5phosphate, dTMP) ( Figure 1) is an essential metabolite required for deoxyribonucleic acid (DNA) synthesis and repair. Thymidylate can be synthesised through a salvage pathway or de novo through a folatedependent pathway. Thymidylate synthesis through both the salvage and de novo pathways occurs in the nucleus and mitochondria. Thymidylate biosynthesis in the nucleus functions during DNA replication and repair. Thymidylate synthesis occurs at a greater rate during DNA replication when cells are in Sphase of the cell cycle. De novo thymidylate biosynthesis is impaired by folate or vitamin B12 deficiency. Impaired de novo thymidylate biosynthesis causes uracil misincorporation into DNA and DNA instability. Thymidylate synthesis enzymes have been successfully targeted by chemotherapeutic agents for treatment of several types of cancers. Common polymorphisms in the TYMS gene are associated with cancer risk. Inhibition of thymidylate biosynthesis can cause a class of common birth defect known as neural tube defects, as well as severe combined immune deficiency (SCID) and megaloblastic anaemia.

author list (cited authors)

  • Field, M. S., Stover, P. J., & Kisliuk, R.

citation count

  • 0

complete list of authors

  • Field, Martha S||Stover, Patrick J||Kisliuk, Roy

Book Title

  • Encyclopedia of Life Sciences

publisher