Thymidylate synthase folate dependence

Thymidylate synthase [EC 2.1.1.45] reductively methylates 2 -deoxyuridine-5 -monophosphate to form 2 -deoxythymidine-5 -monophosphate in the following folate-dependent reaction dUMP + A, A -methylene-tetrahydrofolate dTMP + dihydrofolate. 

Dihydrofolate Reductase. The reduced form of folate (tetrahydrofolate) acts as a one-carbon donor in a wide variety of biosynthetic transformations. This includes essential steps in the synthesis of purine nucleotides and of thymidylate, essential precursors to EHA and I A. For this reason, folate-dependent enzymes have been useful targets for the development of anticancer and anti-inflammatory drugs Ce.g., methotrexate) and anti-infectives (trimethoprim, pyrimethamine). During the reaction catalyzed by thymidylate synthase (TS), tetrahydrofolate also acts as a reducltant and is converted stoichiometrically to dihydrofolate. The regeneration of tetrahydrofolate, required for the continuous fimc-tioning of this cofactor, is catalyzed by dihydrofolate reductase (DHFR). 

Multitargeted antifolate disrupts folate-dependent processes essential for cell reproduction. Inhibits thymidylate synthase, dihydrofolate reductase [DHFR], and glycinamide ribonucleotide formyltransferase [CARET], all involved in synthesis of thymidine and purine nucleotides. 

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