From the Guidelines
The answer is E- thymidylate synthase (TS), as it is the enzyme that catalyzes the reaction of converting 2-monodeoxyuridene-5-monophosphate (dUMP) to 2-deoxythymidine-5-monophosphate (dTMP) in the presence of the methyl donor 5,10-methylene-tetrahydrofolate (CH2-THF). This reaction is crucial for DNA synthesis and cell proliferation, as TS is the rate-limiting step in the biosynthesis of thymidine, one of the four nucleotides required for DNA synthesis 1. Some key points to consider are:
- TS is inhibited by FdUMP, which is formed by thymidine phosphorylase and thymidine kinase action on FU 1.
- The interaction between FU and TS is critical, and other major participants in the analysis of FU effects include DPD and TP 1.
- While dihydrofolate reductase (option A) and methionine synthase (option D) are important enzymes in related pathways, they are not directly necessary for the reaction catalyzed by TS.
- Vitamin B6 (option B) and B12 (option C) are important cofactors for various enzymatic reactions, but they are not directly involved in the reaction catalyzed by TS.
From the FDA Drug Label
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one- carbon groups in the synthesis of purine nucleotides and thymidylate.
The necessary component for this reaction is A- Dihydrofolate reductase. This enzyme is crucial for the conversion of dihydrofolates to tetrahydrofolates, which are then used in the synthesis of purine nucleotides and thymidylate. 2
From the Research
Necessary Components for the Reaction
The reaction in question appears to be related to thymidylate synthesis. Based on the provided evidence, the necessary components for this reaction can be identified as follows:
- Thymidylate synthase: This enzyme is crucial for the conversion of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP) 3, 4, 5, 6.
- Dihydrofolate reductase: This enzyme is involved in the regeneration of tetrahydrofolate, which is necessary for the thymidylate synthase reaction 7.
- Methionine synthase is not directly involved in the thymidylate synthesis reaction, but it is related to the folate cycle 7.
- B6 (pyridoxine) and B12 (cobalamin) are important for various enzymatic reactions, but they are not directly mentioned as necessary for thymidylate synthesis in the provided evidence.
Key Enzymes and Cofactors
The key enzymes and cofactors involved in the reaction are:
- Thymidylate synthase (TS)
- Dihydrofolate reductase (DHFR)
- The folate cofactors, such as 5,10-methylene-tetrahydrofolate (CH2-THF)
Reaction Mechanism
The reaction mechanism involves the conversion of dUMP to dTMP, which is catalyzed by thymidylate synthase. The necessary components for this reaction include thymidylate synthase, dihydrofolate reductase, and the folate cofactors. The correct answer is E- thymidylate synthase, as it is the enzyme directly responsible for the conversion of dUMP to dTMP. Additionally, dihydrofolate reductase (A) is also necessary for the reaction, as it regenerates the tetrahydrofolate cofactor.