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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
    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
  2. 2
    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

    open access unreviewed
  3. 3
    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
  4. 4
    Integrative Analysis Reveals Multi-Target Associations of Liquid Crystal Monomer in Ovulatory Dysfunction: Insights from Composite and Subtype-Specific Mendelian Randomization.

    Pu Y, Xie Y, Li C. · 2026-08-12

    unreviewed
  5. 5
    In Vitro Single-Cell Transcriptomic Profiling of Cultured Stem Cells From Apical Papilla and Dental Pulp Stem Cells: Unveiling Cellular Heterogeneity.

    Shah MS, Sayegh MA, Khalil MM, Sundarabupathi M, AlKhnbashi O, Samaranayake L, Khyriem C, Sultana M, Egusa H,… · 2026-05-05

    open access unreviewed
  6. 6
    Expression of Thymidylate Synthase in Cancer: A Tissue Microarray Study Involving 17,371 Cancers from 136 Tumor Entities.

    Lutz F, Hannemann LS, Büyücek S, Möller K, Viehweger F, Schlichter R, Luebke AM, Kluth M, Hube-Magg C, Hinsch… · 2026-07-16

    unreviewed
  7. 7
    Exploring Methyl-4-hydroxybenzoate-associated CDK1 dysregulation in breast cancer: A multi-omics investigation combining network toxicology, transcriptomics, and molecular dynamics.

    Wang Y, Li J, Liu Z, Ding Y, Li H. · 2026-07-17

    unreviewed
  8. 8
    Machine learning-based identification of lactate metabolism-associated biomarkers in non-alcoholic fatty liver disease.

    Wang X, Wang X, Zhao L, Song L. · 2026-07-21

    unreviewed
  9. 9
    Fluoropyrimidine Cardiotoxicity: Role of Uridine Triacetate and Pharmacogenomic Insights from a Case of 5-FU-Induced Cardiogenic Shock.

    Filomia S, Del Buono MG, Saponara G, Aurigemma C, Marano R, Moliterno E, Tortora G, Minucci A, Salvatore L, S… · 2026-07-06

    unreviewed
  10. 10
    Exploring the molecular association between Di(2-ethylhexyl)phthalate and dilated cardiomyopathy based on interpretable machine learning and molecular docking.

    Xia X, Hu L, Tao S, Li J, Huang X. · 2026-01-22

    unreviewed

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