What enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) in pyrimidine synthesis?

From the Guidelines

Thymidylate synthase is the enzyme that catalyzes the conversion of dUMP to dTMP in pyrimidine synthesis. This reaction is a critical step in the de novo pathway for thymidylate production, which is essential for DNA synthesis and cell replication. During this reaction, thymidylate synthase transfers a methyl group to the 5-position of the uracil ring in dUMP, converting it to thymine in dTMP. The methyl donor for this reaction is 5,10-methylenetetrahydrofolate, which is oxidized to dihydrofolate in the process, as described in the study by 1.

This reaction is particularly important as it provides the only de novo source of thymidylate for DNA synthesis, making thymidylate synthase a common target for anticancer drugs like 5-fluorouracil and methotrexate, which inhibit this pathway to prevent cancer cell proliferation, as further explained in the study by 1. The correct answer can be identified by understanding the role of thymidylate synthase in pyrimidine synthesis, which is supported by the provided evidence.

Some key points to consider include:

• Thymidylate synthase is the rate-limiting step in the biosynthesis of thymidine, one of the four nucleotides required for DNA synthesis and cell proliferation, as noted in 1.
• The enzyme produces de novo 2-deoxythymidine-5-monophosphate (dTMP) by methylation of 2-monodeoxyuridene-5-monophosphate (dUMP) in the presence of the methyl donor 5,10-methylene-tetrahydrofolate (CH2-THF), as described in 1.
• Thymidylate synthase is inhibited by FdUMP, which is formed by thymidine phosphorylase and thymidine kinase action on FU, as explained in 1.

Overall, the evidence supports the conclusion that thymidylate synthase is the enzyme responsible for catalyzing the conversion of dUMP to dTMP in pyrimidine synthesis, as stated in the study by 1.

From the Research

Enzyme Catalyzing dUMP to dTMP Conversion

• The enzyme that catalyzes the conversion of dUMP to dTMP in pyrimidine synthesis is Thymidylate synthase 2, 3, 4, 5, 6.

Key Features of Thymidylate Synthase

• Thymidylate synthase (EC 2.1.1.45) is a critical target for chemotherapeutic agents such as fluoropyrimidines and folic acid analogues 2.
• The enzyme catalyzes the reductive methylation of dUMP by CH2H4folate to produce dTMP and H2folate 3.
• Thymidylate synthase is structurally distinct in different organisms, such as Mycobacterium tuberculosis, making it an attractive drug target 4.

Mechanism of Action

• Thymidylate synthase catalyzes the conversion of dUMP to dTMP through a reductive methylation reaction 3, 5.
• The enzyme's catalytic mechanism involves the binding of dUMP and CH2H4folate, followed by the transfer of a methyl group to form dTMP and H2folate 3.

Inhibition of Thymidylate Synthase

• Thymidylate synthase is inhibited by various agents, including fluoropyrimidines and folic acid analogues, which bind to the active site of the enzyme and prevent catalysis 2, 5.
• Inhibition of thymidylate synthase leads to a deficiency in dTMP, resulting in cell death 5.