TYMS

TYMS, or thymidylate synthase, is a cytosolic enzyme that catalyzes the conversion of deoxyuridylate (dUMP) to deoxythymidylate (dTMP) using 5,10-methylene-tetrahydrofolate (5,10-CH2-THF) as a one-carbon donor, producing dihydrofolate in the process. This reaction provides the sole de novo source of dTMP for DNA synthesis, making TYMS essential for DNA replication and repair. The enzyme typically functions as a homodimer, and the catalytic mechanism involves formation of a covalent intermediate at the active site.

In humans, TYMS is encoded by the TYMS gene. Expression is cell-cycle–regulated, with higher levels in proliferating cells, especially during S phase. A well-studied promoter polymorphism, a variable-number tandem repeat in the promoter enhancer region, influences TYMS transcription; alleles with more repeats (3R) generally drive higher expression than those with fewer (2R), affecting cellular sensitivity to antifolate–antimetabolite therapies.

Clinical significance of TYMS centers on cancer chemotherapy. TYMS is the primary target of 5-fluorouracil (5-FU); the active metabolite FdUMP inhibits TYMS by forming a stable ternary complex with 5,10-CH2-THF, reducing dTMP synthesis and causing thymidine depletion and DNA damage. Leucovorin is often co-administered to boost this effect. Other antifolates, such as pemetrexed and raltitrexed, also inhibit TYMS as part of multi-target regimens. Overexpression or gene amplification of TYMS can confer resistance to 5-FU, while low expression can increase sensitivity, making TYMS a biomarker for antimetabolite therapy response. In bacteria, thymidylate synthase exists in different families (ThyA and ThyX) and remains an antimicrobial target in some contexts.