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rate-limiting unreviewed

Thymidylate synthase (TYMS)

3 reactions · 3 pathways

Cofactors used

THF (folate) · B9 (Folate)

Clinical / pharmacological. Target of 5-fluorouracil (via FdUMP)

What it does, reaction by reaction

3 reactions

One-Carbon Metabolism (Folate Cycle) Amino Acid & Nitrogen Metabolism · Cytosol + mitochondrion

step 6 Irreversible

5,10-Methylene-THF + dUMP → dTMP + DHF

Converts 5,10-Methylene-THF dUMP into dTMP Dihydrofolate (DHF)

› Notes

Thymidylate synthase transfers and reduces a one-carbon unit to form dTMP, generating DHF. This is the committed one-carbon donation step for de novo thymidylate synthesis and is effectively irreversible; THF must be regenerated by DHFR for sustained DNA synthesis.

Deoxyribonucleotide Formation (Ribonucleotide Reductase pathway and thymidylate synthesis) Nucleotide Metabolism · Cytosol

step 6 Irreversible

dUMP → dTMP

Converts dUMP into dTMP

› Notes

Thymidylate synthase (TYMS) catalyzes dUMP + 5,10-methylene-THF → dTMP + DHF. An active-site cysteine forms a covalent intermediate with dUMP, and 5,10-methylene-THF provides the methylene group and the reducing hydride equivalent; this is the committed, effectively irreversible step of de novo dTMP synthesis.

Pyrimidine De Novo Synthesis (through to UMP, then CTP/dTMP) Nucleotide Metabolism · Cytosol (one mitochondrial step)

step 13 Irreversible

dUMP → dTMP

Converts dUMP into dTMP

› Notes

Thymidylate synthase (TYMS) catalyzes dUMP + 5,10-methylene-THF → dTMP + dihydrofolate (DHF). 5,10-Methylene-THF donates both the one-carbon unit and the reducing equivalents for conversion of C5 of uracil to the methyl group of thymine. This reaction is effectively irreversible and is the committed step in de novo thymidylate synthesis.

Showing all 3 reactions.

What accelerates and inhibits it

Regulation is pathway-specific, so each context is listed separately

3 entries

Deoxyribonucleotide Formation (Ribonucleotide Reductase pathway and thymidylate synthesis)

Listed there as: Thymidylate synthase

Accelerated by

dUMP and 5,10-methylene-THF availability

Inhibited by

5-fluoro-dUMP (stable covalent ternary complex with 5,10-methylene-THF); product/pool feedback by dTMP/dTTP

Hormonal control

S-phase/E2F-associated induction in proliferating cells rather than a direct hormonal switch.

One-Carbon Metabolism (Folate Cycle)

Listed there as: Thymidylate synthase

Accelerated by

dUMP and 5,10-methylene-THF availability

Inhibited by

5-fluoro-dUMP (with reduced folate forms); folate deficiency

Hormonal control

Upregulated with cell-cycle/proliferative signaling rather than a single systemic hormone

Pyrimidine De Novo Synthesis (through to UMP, then CTP/dTMP)

Listed there as: Thymidylate synthase

Accelerated by

dUMP and 5,10-methylene-THF availability

Inhibited by

dTMP/dTTP feedback at the pathway level; 5-fluoro-dUMP forms a stable inhibitory ternary complex

Hormonal control

Cell-cycle-dependent expression is increased in S phase through E2F-associated proliferation programs, rather than direct endocrine allostery.

Recent literature

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