[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Thymidylate synthase

[Biochemistry](https://durgical.com/en/biochemistry/) · Enzyme

# Thymidylate synthase

Thymidylate synthase makes dTMP, the thymine building block that only DNA needs. Fluorouracil blocks it.

Updated 2026-11-01

Loading the 3D model…

## 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.

**Also called**
TS

**EC number**
[2.1.1.45](https://www.enzyme-database.org/query.php?ec=2.1.1.45)

**Genes**
TYMS

**Structure (PDB)**
[6QXG](https://www.rcsb.org/structure/6QXG)

## 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

- [Fluorouracil](https://durgical.com/en/pharmacology/fluorouracil/)

## Pathways

- [Pyrimidine synthesis](https://durgical.com/en/biochemistry/pathways/pyrimidine-synthesis/)

## Related conditions

- [Colorectal cancer](https://durgical.com/en/conditions/colorectal-cancer/)
- [Breast cancer](https://durgical.com/en/conditions/breast-cancer/)
- [Gastric cancer](https://durgical.com/en/conditions/gastric-cancer/)
- [Pancreatic cancer](https://durgical.com/en/conditions/pancreatic-cancer/)

## Related

- [Dihydrofolate reductase (DHFR)](https://durgical.com/en/biochemistry/enzymes/dihydrofolate-reductase/)

## 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.

[Add to my cards (3)](https://durgical.app/estudiar/?add=/en/biochemistry/enzymes/thymidylate-synthase/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [TYMS: Thymidylate synthase (human)](https://rest.uniprot.org/uniprotkb/P04818.txt) (UniProt, 2026); [6QXG: Crystal structure of His-tag human thymidylate synthase (HT-hTS) in complex with FdUMP](https://www.rcsb.org/structure/6QXG) (RCSB Protein Data Bank, 2026); [FLUOROURACIL injection, solution](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b34cbf2-66f9-48a4-b41f-deb84ba8e8c4) (DailyMed, US National Library of Medicine, 2026); [Fluorouracil Injection: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a682708.html) (MedlinePlus, US National Library of Medicine, 2026); [Dihydropyrimidine dehydrogenase deficiency: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/dihydropyrimidine-dehydrogenase-deficiency/) (MedlinePlus, US National Library of Medicine, 2026).

[← All of biochemistry](https://durgical.com/en/biochemistry/)

## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake

Representative model, for educational purposes only.

---
Source: https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/enzymes/thymidylate-synthase/