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The enzyme that makes the thymine building block of DNA. Fluorouracil, capecitabine and pemetrexed jam it, starving dividing cells of thymidine.
Thymidylate synthase methylates dUMP to dTMP, the only de novo source of thymidine for DNA synthesis. Fluorouracil, given directly or as the oral prodrug capecitabine, is converted to FdUMP, which forms a stable ternary complex with the enzyme and its folate cofactor; leucovorin (folinic acid) is added to stabilise that complex, which is why FOLFOX and FOLFIRI include it. Pemetrexed inhibits thymidylate synthase alongside other folate enzymes. High tumour TYMS expression is associated with fluoropyrimidine resistance, and DPD deficiency causes severe fluoropyrimidine toxicity.
In plain words · The enzyme that makes the thymine building block of DNA. Fluorouracil, capecitabine and pemetrexed jam it, starving dividing cells of thymidine.
The enzyme that makes the thymine building block of DNA. Fluorouracil, capecitabine and pemetrexed jam it, starving dividing cells of thymidine.
Folate-dependent enzyme converting dUMP to dTMP; inhibited by FdUMP in a ternary complex with 5,10-methylenetetrahydrofolate.
4 products aim at Thymidylate synthase (TYMS): small molecules and degraders. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Lineage antigen shared with normal bone marrow cells and lymphoid tissue cells: HPA finds the gene tissue enhanced in bone marrow, lymphoid tissue, and the 7 medicines aimed at it (Fluorouracil (5-FU), Capecitabine, Pemetrexed and more) act on the wild-type protein, so the normal lineage is hit too. HPA TYMS: RNA tissue enhanced (bone marrow 84 nTPM, lymphoid tissue 106 nTPM); blood lineage group enriched (NK-cells 7 nTPM, T-cells 14 nTPM); high antibody staining in 4 normal tissues; highest cancer staining head and neck cancer (1 of 4 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Colorectal cancer, Gastric & gastro-oesophageal junction cancer, Pancreatic ductal adenocarcinoma); approvals of single-target medicines aimed at it also list Breast cancer (all types), Hepatocellular carcinoma, Mesothelioma, not counted; Open Targets associates it with 14 specific cancer types at or above 0.5 (dyskeratosis congenita, digenic, non-small cell lung carcinoma, breast cancer, colorectal cancer, dyskeratosis congenita, breast carcinoma and more). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas TYMS tissue; Human Protein Atlas TYMS pathology; Open Targets ENSG00000176890 associations
First described 1985. Earliest sequence paper UniProt cites for the protein: Takeishi et al, Nucleic Acids Res, 1985, "Nucleotide sequence of a functional cDNA for human thymidylate synthase". Source.
Folate-dependent enzyme converting dUMP to dTMP; inhibited by FdUMP in a ternary complex with 5,10-methylenetetrahydrofolate.
RNA: tissue enhanced (bone marrow 84 nTPM, lymphoid tissue 106 nTPM), detected in many normal tissues. Blood: group enriched (NK-cells 7 nTPM, T-cells 14 nTPM).
Medium: Appendix, Cerebral cortex, Gallbladder, Rectum, Stomach.
Medium only: breast cancer, colorectal cancer, endometrial cancer, glioma.
HPA TYMS tissue · HPA TYMS pathology · HPA protein class: FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Metastatic cancer | all% | Housekeeping enzyme present in every dividing cell (thymidine synthesis); not a selection marker, which is why these drugs are given by cancer type rather than by test. |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Doxifluridine is an oral fluorouracil prodrug approved in Japan in 1987 and used in China and Korea for stomach, bowel and breast cancers; capecitabine, which the body turns into doxifluridine, later carried the same idea to the rest of the world.
Floxuridine is a cousin of fluorouracil pumped directly into the liver's artery to treat bowel cancer that has spread to the liver, delivering a very high local dose with little reaching the rest of the body.
Leucovorin is not a cancer drug in itself: it rescues normal tissue after high-dose methotrexate and, given with fluorouracil, makes that chemotherapy work better, which is why it appears in FOLFOX, FOLFIRI and FOLFIRINOX.
Raltitrexed is a three-weekly intravenous antifolate used in Europe, Canada and Australia for advanced bowel cancer, and with cisplatin for mesothelioma, in patients who cannot take fluorouracil.
Query for this target: (TITLE:"Thymidylate synthase" OR ABSTRACT:"Thymidylate synthase" OR TITLE:"TYMS" OR ABSTRACT:"TYMS") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Thymidylate synthase (TYMS), not a curated reading list.
Shares Raltitrexed, Leucovorin (folinic acid), Fluorouracil (5-FU), Colorectal cancer.
Shares Floxuridine, Leucovorin (folinic acid), Fluorouracil (5-FU), Colorectal cancer.
Shares Floxuridine, Leucovorin (folinic acid), Fluorouracil (5-FU), Colorectal cancer.
Shares Floxuridine, Capecitabine, Colorectal cancer.
Shares Raltitrexed, Leucovorin (folinic acid), Fluorouracil (5-FU), Capecitabine.
Shares GART (trifunctional purine synthesis enzyme), Leucovorin (folinic acid), Pemetrexed.
Shares Doxifluridine, Capecitabine.
Shares Leucovorin (folinic acid), Fluorouracil (5-FU), Capecitabine, Gastric & gastro-oesophageal junction cancer.