Thymidylate synthase (TS) and Deoxyribonucleic acid (DNA) (TS/DNA)

Thymidylate synthase (TS) is a critical enzyme in the de novo synthesis of pyrimidine nucleotides, specifically catalyzing the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) using 5,10-methylenetetrahydrofolate as a methyl donor [1]. This process is the rate-limiting step for providing thymidine, a necessary building block for DNA replication and repair [2]. Deoxyribonucleic acid (DNA) serves as a complementary target in this context because the inhibition of TS leads to an accumulation of dUMP, which is subsequently phosphorylated and misincorporated into DNA as dUTP [3]. This misincorporation, along with the lack of available dTMP, causes extensive DNA strand breaks and "thymineless death" in rapidly dividing cells [4]. Consequently, the TS-DNA axis is a major therapeutic target for antimetabolite chemotherapeutic agents like 5-fluorouracil, capecitabine, and pemetrexed, which are widely used to treat colorectal, breast, and lung cancers [5]. Clinical efficacy and safety are often influenced by the expression levels of TS and genetic variations in metabolic enzymes such as dihydropyrimidine dehydrogenase [6].

Other names

TYMSThymidylate synthetaseTSDNADeoxyribonucleic acid

Inhibition of thymidylate synthase (TS) prevents dTMP synthesis, leading to dUMP accumulation and subsequent misincorporation of uracil into DNA, causing strand breaks and apoptosis.