Thymidylate (dTMP -> dTTP) synthesis; thymidylate synthase / dUTPase / dTMP kinase

Thymidylate synthesis is the route that makes the DNA-specific precursor dTTP, distinguishing DNA (thymine) from RNA (uracil) precursors. dUTP diphosphatase (DUT) hydrolyses dUTP to dUMP + diphosphate, which both keeps the cellular dUTP:dTTP ratio low (preventing mutagenic uracil misincorporation into DNA) and supplies dUMP as substrate. Thymidylate synthase (TYMS) then reductively methylates dUMP to dTMP, using 5,10-methylenetetrahydrofolate as the one-carbon donor (oxidised to dihydrofolate, regenerated by DHFR) — the sole de novo source of dTMP. Thymidylate kinase (DTYMK) phosphorylates dTMP to dTDP, the essential step common to both the de novo and salvage routes; nucleoside diphosphate kinase then makes dTTP. This pathway is a central target of chemotherapy — TYMS is inhibited by the 5-fluorouracil metabolite FdUMP and by antifolates (raltitrexed, pemetrexed), and the folate cofactor supply is targeted by methotrexate — because rapidly dividing cells depend on de novo dTTP for DNA replication. Perturbing the balance (e.g. DUT loss, TYMS inhibition) causes dUTP accumulation, uracil misincorporation and DNA damage.

MODULE:thymidylate_synthesisDRAFTMetabolic Pathwaymodules/thymidylate_synthesis.yaml
dTMP biosynthetic processGO:0006231
GO:0006231
dTMP biosynthetic process
The module is grounded in the GO dTMP biosynthetic process (GO:0006231) and its continuation to dTTP: dUTP -> dUMP -> dTMP -> dTDP.
Reactome:R-HSA-73605
conversion of dUMP to dTMP
Reactions follow the human Reactome pyrimidine reactions R-HSA-73666 (DUT), R-HSA-73605 (TYMS) and R-HSA-73635 (DTYMK).
file:human/DUT/DUT-ai-review.yaml
DUT gene review (human)
The dUTP -> dUMP step (UniProtKB:P33316, GO:0004170) matches the completed human DUT review.
file:human/TYMS/TYMS-ai-review.yaml
TYMS gene review (human)
The dUMP -> dTMP step (UniProtKB:P04818, GO:0004799) matches the completed human TYMS review.
file:human/DTYMK/DTYMK-ai-review.yaml
DTYMK gene review (human)
The dTMP -> dTDP step (UniProtKB:P23919, GO:0004798) matches the completed human DTYMK review.
4Nodes
3Parts
0Variant Sets
0Variants
3Annotons
2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:thymidylate_synthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (3/3 grounded genes reviewed)

3 complete review(s) · 0 with deep research · 0 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
DTYMK P23919 ✓ ✓ ✗
DUT P33316 ✓ ✓ ✗
TYMS P04818 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Thymidylate (dTMP -> dTTP) synthesisMetabolic Pathwaythymidylate_synthesis
dTMP biosynthetic processGO:0006231
Context
cytosolGO:0005829

Thymidylate (dTMP -> dTTP) synthesis grounded to the human enzymes DUT (UniProtKB:P33316, GO:0004170, EC 3.6.1.23), thymidylate synthase TYMS (P04818, GO:0004799, EC 2.1.1.45) and thymidylate kinase DTYMK (P23919, GO:0004798, EC 2.7.4.9). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over orthologs) with the human enzyme as representative. The pathway converts dUTP -> dUMP -> dTMP -> dTDP, with dTDP then phosphorylated to dTTP by nucleoside diphosphate kinase (NME family, not modelled here). It is tightly coupled to folate one-carbon metabolism (TYMS consumes 5,10-methylene-THF and releases DHF, regenerated by DHFR) and is the pre-eminent antiproliferative drug target: 5-fluorouracil (via FdUMP) and antifolates (raltitrexed, pemetrexed) inhibit TYMS, and methotrexate depletes the folate cofactor. dUMP also arises by salvage/deamination routes, and dTMP by thymidine salvage (TK1/TK2), which feed the same DTYMK step. Loss of the dUTPase gate (DUT) or TYMS inhibition raises dUTP and causes uracil misincorporation / DNA damage. Disease relevance is largely pharmacologic/pharmacogenetic; DTYMK has been linked to a severe neurodevelopmental disorder.

Connections

dut_step -> tyms_step Provides Input For
The dUMP from DUT is the thymidylate-synthase substrate.
tyms_step -> dtymk_step Provides Input For
The dTMP from TYMS is phosphorylated by DTYMK.
Part 1: dUTP hydrolysis (supplies dUMP; blocks uracil misincorporation)
dUTP + H2O to dUMP + diphosphateReactiondut_step

Annotons

DUT: dUTP diphosphatase (dUTPase)
dut_activity
Participant: Family: dUTP diphosphatase family (DUT)
Family:
dUTP diphosphatase family (DUT)PANTHER:PTHR11241
Representative Members: DUT (human)UniProtKB:P33316

Function

dUTP diphosphatase activityGO:0004170
Substrates: dUTP water
Products: dUMP diphosphate

Locations

cytosolGO:0005829

Hydrolyses dUTP to dUMP + PPi (nuclear and mitochondrial isoforms), preventing mutagenic uracil misincorporation into DNA and feeding dUMP to thymidylate synthase.

Part 2: reductive methylation of dUMP to dTMP (de novo)
dUMP + 5,10-methylene-THF to dTMP + dihydrofolateReactiontyms_step

Annotons

TYMS: thymidylate synthase
tyms_activity
Participant: Family: Thymidylate synthase family (TYMS)
Family:
Thymidylate synthase family (TYMS)PANTHER:PTHR11548
Representative Members: TYMS (human)UniProtKB:P04818

Function

thymidylate synthase activityGO:0004799
Substrates: dUMP 5,10-methylenetetrahydrofolate
Products: dTMP dihydrofolate (DHF)

Locations

cytosolGO:0005829

Homodimer catalysing the sole de novo source of dTMP; couples to folate one-carbon metabolism (produces DHF, regenerated by DHFR). Central 5-FU/ antifolate chemotherapy target; autoregulates its own translation.

Part 3: phosphorylation of dTMP to dTDP
dTMP + ATP to dTDP + ADPReactiondtymk_step

Annotons

DTYMK: thymidylate kinase (dTMP kinase)
dtymk_activity
Participant: Family: Thymidylate kinase family (DTYMK)
Family:
Thymidylate kinase family (DTYMK)PANTHER:PTHR10344
Representative Members: DTYMK (human)UniProtKB:P23919

Function

dTMP kinase activityGO:0004798
Substrates: dTMP ATP
Products: dTDP ADP

Locations

cytosolGO:0005829

Phosphorylates dTMP to dTDP — the rate-limiting step common to both the de novo (TYMS) and salvage (thymidine kinase) routes to dTTP; essential for DNA replication. dTDP is then converted to dTTP by nucleoside diphosphate kinase.