Biochemistry · Enzyme
Thymidylate synthase !
Thymidylate synthase makes dTMP, the thymine building block that only DNA needs. Fluorouracil blocks it.
Updated 2026-11-01
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Key facts
- dUMP + 5,10-methylene-tetrahydrofolate → dTMP + dihydrofolate.
- The folate gives both the one-carbon group and the electrons, so it leaves as dihydrofolate.
- It is the only de novo source of thymidylate: without it the cell cannot copy its DNA.
- DHFR and SHMT1 work next to it to turn the folate back into methylene-tetrahydrofolate.
Structure
- A homodimer of chains 313 residues long.
- Structure 6QXG is human thymidylate synthase holding FdUMP, the active fluorouracil metabolite.
Regulation
- It binds SHMT1 in a DNA-dependent way.
- It forms a complex with DHFR and SHMT1 in the nucleus and in mitochondria for thymidylate synthesis there.
Inhibitors and toxins
- Fluorouracil: becomes FdUMP, which takes the place of dUMP and blocks the enzyme.
- Methotrexate acts one step back, by starving it of reduced folate.
Clinical notes
- Fluorouracil is used against colorectal, breast, stomach and pancreatic cancers, among others.
- Fluorouracil also works through FUTP in RNA and FdUTP in DNA, besides the block of thymidylate synthase.
- It is cleared by dihydropyrimidine dehydrogenase (DPD); people with DPD deficiency can suffer severe or fatal toxicity, so DPYD testing is advised before treatment.
- Leucovorin is added in some regimens.
Drugs that act here
Pathways
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
What does thymidylate synthase make?
dTMP, from dUMP and methylene-tetrahydrofolate; dihydrofolate is left over.
Which fluorouracil metabolite inhibits thymidylate synthase?
FdUMP, which sits in the dUMP site.
Why is DPYD tested before fluorouracil?
DPD clears fluorouracil; with DPD deficiency the drug builds up and causes severe toxicity.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: TYMS: Thymidylate synthase (human) (UniProt, 2026); 6QXG: Crystal structure of His-tag human thymidylate synthase (HT-hTS) in complex with FdUMP (RCSB Protein Data Bank, 2026); FLUOROURACIL injection, solution (DailyMed, US National Library of Medicine, 2026); Fluorouracil Injection: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Dihydropyrimidine dehydrogenase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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