Four steps from UDP: remove the 2' hydroxyl, clear dUTP, then add a methyl group
Route: Uridine diphosphate → Deoxyuridine diphosphate → Deoxyuridine triphosphate → Deoxyuridine monophosphate → Thymidine monophosphate
Ribonucleotide reductase removes the 2' hydroxyl of the ribose of UDP, which makes the sugar a deoxyribose. The reducing power comes from thioredoxin, which ends up oxidized. Nucleoside diphosphate kinase then makes dUTP, and dUTPase splits dUTP at once into dUMP and pyrophosphate. This keeps the dUTP to dTTP ratio low and prevents dUTP from being built into DNA by DNA polymerases. Thymidylate synthase then moves a one-carbon unit from 5,10-methylene-THF to carbon 5 of dUMP and reduces it to a methyl group. The THF is oxidized to dihydrofolate (DHF), and another enzyme, dihydrofolate reductase, must restore it. Because rapidly dividing cells, such as cancer cells, need large amounts of dTMP, thymidylate synthase is a target of cancer drugs such as fluorouracil, which acts through its metabolite FdUMP, and raltitrexed. The enzyme drawn is the human one with raltitrexed bound. The carbon of the methyl group comes from serine, through the glycine pathway.
Practice this pathway All pathways
| Step | Enzyme | EC | In | Out |
|---|---|---|---|---|
| 1 | Ribonucleotide reductase | 1.17.4.1 | Trx-(SH)₂ | Trx-S₂, H₂O |
| 2 | Nucleoside diphosphate kinase | 2.7.4.6 | ATP | ADP |
| 3 | dUTP pyrophosphatase (dUTPase) | 3.6.1.23 | H₂O | PPᵢ |
| 4 | Thymidylate synthase | 2.1.1.45 | 5,10-CH₂-THF | DHF |
Enzyme names and EC numbers are those used on the interactive board. Checked against sources: see the claim table in the repository (tools/pathway_data/checks).