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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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Europe PMC · fetched just now · sorted by publication date

  1. 1
    Elevated miR-103b in exosomes derived from brain-metastatic triple-negative breast cancer cells remodels the brain pre-metastatic niche (PMN).

    Zhou L, Ke J, Zhang S, Xiao S, Zhang H, Liu S, Liu L, Liu M, Lu Z, Zheng S. · 2026-09-25

    open access unreviewed
  2. 2
    Microbiota as a modulator of drug response: targeting microbial-drug crosstalk in cancer therapy.

    Zhao T, Liu M, Qiu L, Zhang H, Zhang N, Liu Z, Xia Z, Luo P, Huang J, Cheng Q. · 2026-04-10

    open access unreviewed
  3. 3
    Exploring the gut microbiome and metabolomic interactions of antimetabolite drugs to optimize therapy.

    Chen J, Wang Y, Xu L, Li X, Zhao L. · 2026-02-27

    cited 1× open access unreviewed
  4. 4
    Machine learning-assisted detection of canine mammary tumors using serum autoantibody signatures.

    Lan B, Chang CY, Liu SW, Wu CC, Lai KM, Liu HP. · 2026-01-21

    cited 1× open access unreviewed
  5. 5
    Synovial Fluid Immune Cell Landscape in Juvenile Idiopathic Arthritis

    Pitkänen V, Lappalainen B, Rytkönen‐Nissinen M, Remes‐Pakarinen T, Vähäsalo P, Möttönen M, Grönlund M, Arvone… · 2026-10-01

    open access unreviewed
  6. 6
    Triazole-Linked Pyrimidine Nucleoside Dimers: Design, Synthesis, and Applications in Medicinal and Nucleic Acid Chemistry. Part IV.

    Baraniak D, Wawrzyniak D, Baranowski D. · 2026-10-01

    open access unreviewed
  7. 7
    ThermoTargetMiner as a proteome integral solubility alteration target database for prospective drugs against lung cancer.

    Lyu H, Gharibi H, Sokolova B, Varli M, Voiland A, Nilsson B, Meng Z, Gaetani M, Saei AA, Zubarev RA. · 2026-10-02

    open access unreviewed
  8. 8
    Gliadin-specific CD4<sup>+</sup> T cells exhibit functional diversity independent of TCR usage or epitope specificity.

    Jones CM, Lim JJ, Schattgen SA, Loh TJ, Dao HT, Tran MT, Nguyen A, Zareie P, Felix NJ, Thomas PG, Hardy MY, T… · 2026-10-02

    open access unreviewed
  9. 9
    Weighted single-step GWAS identified candidate genes associated with semen traits in Rhode Island Red chickens.

    Tesfay HH, Zhang X, Li Y, Zong Y, Ma Z, Han X, Zhao Y, Pan Z, Mani AI, Yang F, Zhang Z, Chen J, Sun Y, Chen J. · 2026-05-28

    open access unreviewed
  10. 10
    HIV-1 prime-boost vaccination shapes distinct clonal trajectories and memory precursor states of Env- and Gag-specific T cells

    · 2026-09-29

    open access unreviewed

External claims. These come from an index outside this database and are not checked against it. Treat them as leads.