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Thus, folate deficiency hinders DNA synthesis and cell division, ..

This paper explores the role of cell cycle phase in L1210 leukemia cells in logarithmic versus stationary phase growth as a factor in the rate and extent of tetrahydrofolate cofactor interconversion to dihydrofolate after exposure of cells to the dihydrofolate reductase inhibitor trimetrexate.

12/02/2016 · Controlling supplies for DNA and RNA synthesis

Finally, in this pathway, many of the enzymes are grouped together on singlepolypeptide chains. This serves to organize and control the processing of asubstrate from one step to the next. Such "chanelling" increases theoverall rate of a pathway and protects intermediates from degradation. Inanimals, the enzymes of the IMP synthesis pathway are grouped as follows:

Controlling supplies for DNA and RNA synthesis

In this reaction, serine is converted to glycine, while one methylene group is covalently linked to THF to form 5,10-methylene-tetrahydrofolate.

Field MS, Kamynina E, Watkins D, et al. (2015) Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proceedings of the National Academy of Sciences of the USA 112: 400–405.

Inhibition of thymidylate synthetase leads to decreased dTTP synthesis and formation of excess dUTP. The dUTP is incorporated into DNA. Repair of this abnormal DNA is blocked by lack of thymidine residues; the DNA breaks apart (karyorrhexis) and the cell dies.

5-methyl-tetrahydrofolate | C20H25N7O6 - PubChem

Methotrexate has no efficacy for dihydrofolate reductase and so greatly reduces the amount of tetrahydrofolate produced.

The normal proliferation of cells depends on adequate folate and vitamin B12. Folate is necessary for efficient thymidilate synthesis and production of DNA.

Thymidylate is a component of DNA (deoxyribonucleic acid), and is synthesised from the or nucleotide salvage pathways. Many cell types rely on the salvage pathway, but often this is insufficient. Thymidylate is synthesised 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 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 double‐strand breaks. Impaired 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.

These two final steps of tetrahydrofolate (6) biosynthesis are common chemotherapeutic targets for antibacterial and antiparasitic agents.
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5-methyl-tetrahydrofolate | C20H25N7O6 ..

However, this was sufficient to interconvert all available tetrahydrofolate cofactors to dihydrofolate (T 1 2 ∼ 2 hr) when dihydrofolate reductase was inhibited by the lipophilic antifolate trimetrexate.


In the present study, we assessed the rate of resumption of thymidylate synthase catalytic activity in terms of [3H]deoxyuridine incorporation into DNA and dihydrofolate generation from tetrahydrofolate cofactors following exposure of cells to fluorodeoxyuridine.

Protein Synthesis and Site of Action of Antimicrobials that ..

Similarly, the lack of tetrahydrofolate inhibits purine synthesis, restricting the production of the amino acids guanine and adenine and thereby also preventing the replication of cancer cells.

including DNA synthesis and red blood cell synthesis

Field MS, Kamynina E, Agunloye OC, et al. (2014) Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. Journal of Biological Chemistry 289: 29642–29650.

Folic Acid and L-5-Methyltetrahydrofolate

These data suggest that an earlier than previously expected depletion of tetrahydrofolate cofactors with consequent inhibition of purine and other folate-dependent synthetic processes is likely to occur when antifolates are administered after a fluoropyrimidine.

Tetrahydrofolic acid - Wikipedia

Field MS, Anguera MC, Page R, et al. (2009) 5,10‐Methenyltetrahydrofolate synthetase activity is increased in tumors and modifies the efficacy of antipurine LY309887. Archives of Biochemistry and Biophysics 481: 145–150.

Tetrahydrofolic acid, or tetrahydrofolate, is a folic acid derivative

Flow cytometric analysis of DNA content indicated that log phase cultures were 53.0% S phase; this decreased to 42.1% at 24 h and 24.1% at 48 h in stationary phase cultures.

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