De novo deoxyribonucleoside triphosphate synthesis by class I ribonucleotide reductase

De novo formation of the four DNA precursors dATP, dGTP, dCTP and dTTP from ribonucleoside diphosphates in eukaryotes and other organisms with a class I (oxygen-dependent) ribonucleotide reductase. The reductase replaces the 2'-hydroxyl of ADP, GDP, CDP and UDP with hydrogen using electrons from thioredoxin or glutaredoxin; its large (alpha) subunit binds substrates and the allosteric effectors that balance the four products, and its small (beta) subunit carries the di-iron tyrosyl radical cofactor. In budding yeast the active enzyme is an alpha2 homodimer of Rnr1 (or the damage-induced Rnr3) with a beta heterodimer of the radical-bearing Rnr2 and the catalytically inactive but essential Rnr4. Nucleoside-diphosphate kinase then phosphorylates dADP, dGDP and dCDP to the triphosphates. dTTP cannot be made by direct reduction: dUMP is produced either by hydrolysis of dUTP by dUTP diphosphatase, which also keeps dUTP out of DNA, or by deamination of dCMP by dCMP deaminase; thymidylate synthase then methylates dUMP to dTMP with 5,10-methylenetetrahydrofolate, dTMP kinase makes dTDP and nucleoside-diphosphate kinase makes dTTP. Activity and subunit levels are tightly controlled by the cell cycle and the DNA damage checkpoint. Class II (adenosylcobalamin) and class III (anaerobic, glycyl-radical) reductases of prokaryotes, deoxynucleoside salvage and the mitochondrial dNTP supply pathway of animals are outside the module.

MODULE:dntp_de_novo_synthesisDRAFTMetabolic Pathwaymodules/dntp_de_novo_synthesis.yaml
deoxyribonucleotide biosynthetic processGO:0009263 dTTP biosynthetic processGO:0006235
YeastPathways:PWY-7220-1
adenosine deoxyribonucleotides de novo biosynthesis II (S. cerevisiae, SGD YeastPathways)
ADP reduction by RNR1-RNR4 and dADP phosphorylation by YNK1. Also lists a gene-less formate-dependent class III reductase reaction (RXN0-745) that does not occur in yeast.
YeastPathways:PWY-7222-1
guanosine deoxyribonucleotides de novo biosynthesis II (S. cerevisiae, SGD YeastPathways)
GDP reduction and dGDP phosphorylation; gene-less class III reaction RXN0-746 as above.
YeastPathways:YEAST-DE-NOVO-PYRMID-DNT
de novo biosynthesis of pyrimidine deoxyribonucleotides (S. cerevisiae, SGD YeastPathways)
CDP and UDP reduction, NDP kinase (YNK1), DUT1, CDC21, CDC8 (dTMP and dUMP kinase), a gene-less dCMP kinase reaction (URA6 in the GO-CAM) and a gene-less dCTP deaminase reaction. S. cerevisiae has no dCTP deaminase; it deaminates dCMP with DCD1, which the frame omits.
GO:0009263
deoxyribonucleotide biosynthetic process
Module-level process term for reduction of NDPs and formation of the dNTPs.
GO:0006235
dTTP biosynthetic process
Process term for the dUMP-to-dTTP branch.
PMID:2199320
Two genes differentially regulated in the cell cycle and by DNA-damaging agents encode alternative regulatory subunits of ribonucleotide reductase.
RNR1 (essential, cell-cycle regulated) and RNR3 (non-essential, strongly DNA-damage inducible) encode alternative large subunits.
PMID:11893751
Yeast DNA damage-inducible Rnr3 has a very low catalytic activity strongly stimulated after the formation of a cross-talking Rnr1/Rnr3 complex.
Rnr3 alone has under 1% of Rnr1 activity but is activated in an Rnr1/Rnr3 heterodimer.
PMID:9315671
Rnr4p, a novel ribonucleotide reductase small-subunit protein.
Rnr4p lacks iron ligands and is catalytically inactive but is required for RNR activity.
PMID:9315670
Identification of RNR4, encoding a second essential small subunit of ribonucleotide reductase in Saccharomyces cerevisiae.
RNR2 and RNR4 are both essential, non-interchangeable and coimmunoprecipitate.
PMID:12732713
Subcellular localization of yeast ribonucleotide reductase regulated by the DNA replication and damage checkpoint pathways.
Rnr1 and Rnr3 are predominantly cytoplasmic, whereas Rnr2 and Rnr4 are nuclear and redistribute to the cytoplasm in S phase or after DNA damage.
PMID:16537480
Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly.
Structural basis of the yeast Rnr1 large subunit and its assembly with the small subunit.
PMID:1659321
Saccharomyces cerevisiae nucleoside-diphosphate kinase: purification, characterization, and substrate specificity.
Yeast NDP kinase phosphorylates dTDP, dUDP, dGDP, dCDP and dADP as well as ribonucleotides.
PMID:8223452
dUTP pyrophosphatase is an essential enzyme in Saccharomyces cerevisiae.
DUT1 is essential; dut1 nulls survive only with exogenous dTMP, and death results from uracil incorporation into DNA.
PMID:21548881
Structure and activity of the Saccharomyces cerevisiae dUTP pyrophosphatase DUT1, an essential housekeeping enzyme.
Biochemical and structural characterisation of DUT1 dUTP hydrolysis.
PMID:3023902
Sequence and expression of the dCMP deaminase gene (DCD1) of Saccharomyces cerevisiae.
DCD1 encodes dCMP deaminase; dcd1 dmp1 haploids are dUMP auxotrophs.
PMID:6094555
Characterization of Saccharomyces cerevisiae thymidylate kinase, the CDC8 gene product. General properties, kinetic analysis, and subcellular localization.
CDC8 thymidylate kinase phosphorylates dTMP (and dUMP more weakly) and is found in the nuclear and cytoplasmic fraction but not in mitochondria.
file:yeast/CDC21/CDC21-ai-review.yaml
S. cerevisiae CDC21 gene review
CDC21 core function is thymidylate synthase activity (GO:0004799) at the nuclear periphery, part of dTMP biosynthesis.
PMID:14500848
Reconstitution of an efficient thymidine salvage pathway in Saccharomyces cerevisiae.
cdc21 deletion strains depend entirely on exogenous thymidine only when a heterologous nucleoside kinase and transporter are supplied, showing that thymidylate synthase is the sole native dTMP source.
PMID:15157888
In vivo labeling of fission yeast DNA with thymidine and thymidine analogs.
Yeasts neither take up thymidine efficiently nor phosphorylate it, so fission yeast also depends on thymidylate synthase for dTMP.
10Nodes
7Parts
1Variant Sets
2Variants
7Annotons
6Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:dntp_de_novo_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.

Function consistency and core coverage

9 gene-function check(s) reflected in core functions · 0 conflict(s) · 8 evidence or coverage gap(s) (23 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
class_i_rnr_activity PROTEIN_COMPLEX
Gene 		ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
GO:0004748 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
dndp_kinase_activity YNK1 (Saccharomyces cerevisiae)
UniProtKB:P36010
Family Representative 		nucleoside diphosphate kinase activity
GO:0004550 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dndp_kinase_activity NME1 (human)
UniProtKB:P15531
Family Representative 		nucleoside diphosphate kinase activity
GO:0004550 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dutpase_activity DUT1 (Saccharomyces cerevisiae)
UniProtKB:P33317
Family Representative 		dUTP diphosphatase activity
GO:0004170 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dutpase_activity DUT (human)
UniProtKB:P33316
Family Representative 		dUTP diphosphatase activity
GO:0004170 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dutpase_activity dut (Escherichia coli K-12)
UniProtKB:P06968
Family Representative 		dUTP diphosphatase activity
GO:0004170 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dcmp_deaminase_activity DCD1 (Saccharomyces cerevisiae)
UniProtKB:P06773
Family Representative 		dCMP deaminase activity
GO:0004132 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dcmp_deaminase_activity DCTD (human)
UniProtKB:P32321
Family Representative 		dCMP deaminase activity
GO:0004132 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
thymidylate_synthase_activity CDC21 (Saccharomyces cerevisiae)
UniProtKB:P06785
Family Representative 		thymidylate synthase activity
GO:0004799 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thymidylate_synthase_activity TYMS (human)
UniProtKB:P04818
Family Representative 		thymidylate synthase activity
GO:0004799 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thymidylate_synthase_activity thyA (Escherichia coli K-12)
UniProtKB:P0A884
Family Representative 		thymidylate synthase activity
GO:0004799 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dtmp_kinase_activity CDC8 (Saccharomyces cerevisiae)
UniProtKB:P00572
Family Representative 		dTMP kinase activity
GO:0004798 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dtmp_kinase_activity DTYMK (human)
UniProtKB:P23919
Family Representative 		dTMP kinase activity
GO:0004798 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dtmp_kinase_activity tmk (Escherichia coli K-12)
UniProtKB:P0A720
Family Representative 		dTMP kinase activity
GO:0004798 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dtdp_ndp_kinase_activity YNK1 (Saccharomyces cerevisiae)
UniProtKB:P36010
Family Representative 		nucleoside diphosphate kinase activity
GO:0004550 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dtdp_ndp_kinase_activity NME1 (human)
UniProtKB:P15531
Family Representative 		nucleoside diphosphate kinase activity
GO:0004550 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dndp_kinase_activity nucleoside-diphosphate kinases (NDK/NME)
PANTHER:PTHR11349
Family 		nucleoside diphosphate kinase activity
GO:0004550 		Family Function Unreviewed
Family review leaves GO:0004550 UNRESOLVED. Awd and classical NDKs catalyze nucleoside-diphosphate phosphorylation; the Awd killer-of-prune mutation changes protein stability without abolishing catalytic efficiency (PMID:1320004). The classification also includes NDK-like/domain-containing branches for which this source does not resolve a complete active-site and biochemical boundary. Awd activity is supported, but an unconditional grant to all classified NDK-like proteins remains unresolved. Notch regulation and other Awd-specific pathways are not universal NDK functions.
dutpase_activity dUTPases (Dut)
PANTHER:PTHR11241:SF0
Family 		dUTP diphosphatase activity
GO:0004170 		Family Supported
Family review supports GO:0004170 for PANTHER:PTHR11241:SF0. The activity both the dNTP and the thymidylate-synthesis modules assert for this family. It is safe for SF0 (all characterized cellular dUTPases, including yeast DUT1) and SF11 (human DUT). It is not to be assumed for SF12, which PANTHER labels inactive. SF8 and the other subfamilies were not examined.
dutpase_activity dUTPases (Dut)
PANTHER:PTHR11241:SF11
Family 		dUTP diphosphatase activity
GO:0004170 		Family Supported
Family review supports GO:0004170 for PANTHER:PTHR11241:SF11. The activity both the dNTP and the thymidylate-synthesis modules assert for this family. It is safe for SF0 (all characterized cellular dUTPases, including yeast DUT1) and SF11 (human DUT). It is not to be assumed for SF12, which PANTHER labels inactive. SF8 and the other subfamilies were not examined.
dcmp_deaminase_activity dCMP deaminases
PANTHER:PTHR11086:SF18
Family 		dCMP deaminase activity
GO:0004132 		Family Supported
Family review supports GO:0004132 for PANTHER:PTHR11086:SF18. The activity the dNTP module asserts for PTHR11086:SF18. It is safe for SF18, the characterized dCMP deaminases, with the caveat that B. subtilis ComEB is uncharacterized. It is not safe for SF14 (CDADC1), a dCTP deaminase.
thymidylate_synthase_activity ThyA-type thymidylate synthases
PANTHER:PTHR11548
Family 		thymidylate synthase activity
GO:0004799 		Family Supported
Family review supports GO:0004799 FAMILY_WIDE. This is the defining activity, shared by bacterial ThyA, fungal CDC21, the TS domain of S. pombe hal3, animal TYMS and the TS domains of the plant and protist DHFR-TS proteins. Both modules that use this family (dntp_de_novo_synthesis and thymidylate_synthesis) assert exactly this term. Two phage members of SF1, the SPO1 and M6 dUMP hydroxymethylases, are exceptions.
dtmp_kinase_activity thymidylate kinases
PANTHER:PTHR10344
Family 		dTMP kinase activity
GO:0004798 		Family Supported
Family review supports GO:0004798 FAMILY_WIDE. This is the defining activity of the bacterial, viral and eukaryotic thymidylate kinases. Both modules that use the family (dntp_de_novo_synthesis with CDC8, DTYMK and E. coli tmk; thymidylate_synthesis with DTYMK) assert it, and all their representative members are true TMPKs. Vertebrate CMPK2 (SF4) is an exception: PAINT pruned it with an IRD, and its characterized substrates are dUMP, dCMP, CMP and UMP.
dtdp_ndp_kinase_activity nucleoside-diphosphate kinases (NDK/NME)
PANTHER:PTHR11349
Family 		nucleoside diphosphate kinase activity
GO:0004550 		Family Function Unreviewed
Family review leaves GO:0004550 UNRESOLVED. Awd and classical NDKs catalyze nucleoside-diphosphate phosphorylation; the Awd killer-of-prune mutation changes protein stability without abolishing catalytic efficiency (PMID:1320004). The classification also includes NDK-like/domain-containing branches for which this source does not resolve a complete active-site and biochemical boundary. Awd activity is supported, but an unconditional grant to all classified NDK-like proteins remains unresolved. Notch regulation and other Awd-specific pathways are not universal NDK functions.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • dttp_branch ⊣ ribonucleotide_reduction [closed]
    dttp_branch is regulated by dndp_phosphorylation: feedback loop closed

Gene-review completeness (12/21 grounded genes reviewed)

12 complete review(s) · 9 with deep research · 9 missing review · 3 reviewed but lacking deep research

Gene Review Complete Deep research
CDC21 P06785 ✓ ✓ ✓
CDC8 P00572 ✓ ✓ ✓
DCD1 P06773 ✓ ✓ ✓
DTYMK P23919 ✓ ✓ ✗
DUT P33316 ✓ ✓ ✗
DUT1 P33317 ✓ ✓ ✓
nrdA (Escherichia coli K-12) P00452 ✗ — —
dut (Escherichia coli K-12) P06968 ✗ — —
tmk (Escherichia coli K-12) P0A720 ✗ — —
thyA (Escherichia coli K-12) P0A884 ✗ — —
NME1 (human) P15531 ✗ — —
RRM1 (human) P23921 ✗ — —
RRM2 (human) P31350 ✗ — —
DCTD (human) P32321 ✗ — —
nrdB (Escherichia coli K-12) P69924 ✗ — —
RNR1 P21524 ✓ ✓ ✓
RNR2 P09938 ✓ ✓ ✓
RNR3 P21672 ✓ ✓ ✓
RNR4 P49723 ✓ ✓ ✓
TYMS P04818 ✓ ✓ ✗
YNK1 P36010 ✓ ✓ ✓

Details

Context
EukaryotaNCBITaxon:2759
cytosolGO:0005829
De novo dNTP synthesis (class I ribonucleotide reductase and the dTTP branch)Metabolic Pathwaydntp_de_novo_synthesis
deoxyribonucleotide biosynthetic processGO:0009263 dTTP biosynthetic processGO:0006235
Context
EukaryotaNCBITaxon:2759
cytosolGO:0005829

NEW module from the YeastPathways crosswalk (PWY-7220-1, PWY-7222-1, YEAST-DE-NOVO-PYRMID-DNT). Scope: class Ia ribonucleotide reduction and dNTP formation in eukaryotes, with S. cerevisiae, human and E. coli exemplars; no PomBase GO-CAM is listed for this group. Reaction assessment: the four NDP reductions are one RNR annoton; the five NDP kinase reactions (dADP, dGDP, dCDP, dUDP, dTDP) are YNK1 annotons in parts 2 and 3. Enzyme corrections: YeastCyc lists a dCTP deaminase reaction (DCTP-DEAM-RXN) without a gene - S. cerevisiae has no dCTP deaminase (no EC 3.5.4.13 protein in UniProt for S288C) and instead deaminates dCMP with DCD1 (PMID:3023902), which the frame omits; DCD1 was added. The dCMP kinase reaction (RXN-7913) has no gene in YeastCyc but URA6 in the GO-CAM (URA6 phosphorylates CMP/dCMP, PMID:1333436); it supplies dCMP-to-dCDP salvage flux and is modelled in pyrimidine_salvage / de_novo_pyrimidine_synthesis rather than here. CDC8 dUMP kinase (RXN-14122) is a minor side activity (PMID:6094555). The formate-dependent class III reductase reactions RXN0-745/RXN0-746 listed by YeastCyc with no gene do not exist in yeast. GO-CAM disagreements: activities are filed under unrelated processes (GO:0046085 adenosine metabolic process, GO:0106387 'de novo' GMP biosynthesis, GO:0006207 pyrimidine nucleobase biosynthesis) rather than deoxyribonucleotide biosynthesis; CDC21 is placed in cytosol whereas the reviewed location is the nuclear periphery; URA6 carries the obsolete GO:0004127. The RNR is enabled by SGD complex entities CPX-1102 and CPX-1103 (Rnr1- and Rnr3-containing holoenzymes). Out of scope: thioredoxin/glutaredoxin reduction of RNR (TRX1/TRX2, TRR1), regulation by the Mec1-Rad53-Dun1 checkpoint, the Sml1 and Dif1 regulators and Crt1 repression (regulatory, not catalytic steps), class II and III reductases, the human p53-inducible RRM2B small subunit and mitochondrial salvage (mitochondrial_dntp_supply), and deoxynucleoside salvage (pyrimidine_salvage). The dTTP branch overlaps thymidylate_synthesis (human DUT/TYMS/DTYMK; folded into this module in the crosswalk). Thymidylate synthase is the only native dTMP source in budding and fission yeast, which lack thymidine kinase (PMID:14500848, PMID:15157888).

Connections

dADP, dGDP, dCDP and dUDP are phosphorylated to the triphosphates.
dndp_phosphorylation -> dttp_branch Provides Input For
dUTP (from dUDP) is hydrolysed by dUTPase, and dCTP turnover supplies dCMP for dCMP deaminase.
dttp_branch -> ribonucleotide_reduction Negatively Regulates
dTTP binds the specificity site of the large subunit, inhibiting CDP and UDP reduction and promoting GDP reduction (allosteric pool balancing).
Part 1: ribonucleotide reduction
NDP to dNDP (ADP, GDP, CDP, UDP)Reactionribonucleotide_reduction

Annotons

Class Ia ribonucleotide reductase (alpha2 beta2)
class_i_rnr_activity
Participant: Protein Complex: class Ia ribonucleoside-diphosphate reductase complex
Protein Complex:
class Ia ribonucleoside-diphosphate reductase complexGO:0005971 Large-subunit homodimer (R1/alpha) with a small-subunit dimer (R2/beta). In S. cerevisiae the small subunit is the Rnr2-Rnr4 heterodimer, and Rnr3 can replace or pair with Rnr1 after DNA damage.
Active units:
Large (alpha, R1) subunit
Participant: Family: class Ia RNR large subunits
Family:
class Ia RNR large subunitsPANTHER:PTHR11573:SF6 SF6 is the class Ia (eukaryotic/NrdA-type) group; class Ib NrdE is in SF30 (PTHR11573 family review).
Representative Members: RNR1 (Saccharomyces cerevisiae)UniProtKB:P21524 RNR3 (Saccharomyces cerevisiae)UniProtKB:P21672 RRM1 (human)UniProtKB:P23921 nrdA (Escherichia coli K-12)UniProtKB:P00452
Role: Binds the NDP substrate and the specificity and activity effectors; carries the catalytic cysteines that perform 2'-reduction.
Small (beta, R2) radical-bearing subunit
Participant: Family: class I RNR small subunits
Family:
class I RNR small subunitsPANTHER:PTHR23409
Representative Members: RNR2 (Saccharomyces cerevisiae)UniProtKB:P09938 RRM2 (human)UniProtKB:P31350 nrdB (Escherichia coli K-12)UniProtKB:P69924
Role: Generates and stores the di-iron tyrosyl radical that initiates catalysis in the large subunit.
Inactive small-subunit partner (fungal Rnr4 type)
Participant: Gene Product: RNR4 (Saccharomyces cerevisiae)
Gene Product:
RNR4 (Saccharomyces cerevisiae)UniProtKB:P49723 Lacks iron-binding residues; mutation of its tyrosine does not affect function (PMID:9315671); essential and not interchangeable with RNR2 (PMID:9315670).
Role: Catalytically inactive beta-like subunit that heterodimerises with Rnr2 and is required for radical formation and activity in budding yeast; absent from animals and E. coli.

Function

ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptorGO:0004748
Substrates: ADP, GDP, CDP or UDP reduced thioredoxin
Products: dADP, dGDP, dCDP or dUDP oxidized thioredoxin water

Locations

cytosolGO:0005829

Rate-limiting step of dNTP production and the only de novo source of deoxyribose. One allosterically regulated enzyme reduces all four NDPs; the specificity site (dATP/dGTP/dTTP) balances the pools and the activity site (ATP vs dATP) sets overall flux.

Part 2: dNDP phosphorylation
dADP, dGDP and dCDP (and dUDP) to the triphosphatesReactiondndp_phosphorylation

Annotons

Nucleoside-diphosphate kinase (dNDP to dNTP)
dndp_kinase_activity
Participant: Family: nucleoside-diphosphate kinases (NDK/NME)
Family:
nucleoside-diphosphate kinases (NDK/NME)PANTHER:PTHR11349
Representative Members: YNK1 (Saccharomyces cerevisiae)UniProtKB:P36010 NME1 (human)UniProtKB:P15531

Function

nucleoside diphosphate kinase activityGO:0004550
Substrates: dADP, dGDP, dCDP or dUDP ATP
Products: dATP, dGTP, dCTP or dUTP ADP

Broad-specificity terminal phosphorylation. YNK1 is not essential, so other phosphotransferases can supply dNTPs in its absence.

Part 3: dTTP formation via dUMP
dUMP to dTTPMetabolic Pathwaydttp_branch

Thymidylate branch shared with the thymidylate_synthesis module, which models the human DUT, TYMS and DTYMK enzymes.

Connections

Part 1: dUMP formation
dUMP formation from dUTP or dCMPReactiondump_formation
Variant set: dUMP source by substrate route to dUMP (One Or More)

Enterobacteria make most dUMP through dCTP deaminase (dCTP to dUTP), an enzyme absent from yeasts; it is not modelled until a curated exemplar is added.

dUTP hydrolysis by dUTP diphosphataseReactiondutpase_route

Annotons

dUTP diphosphatase
dutpase_activity
Participant: Family: dUTPases (Dut)
Family:
dUTPases (Dut)
Representative Members: DUT1 (Saccharomyces cerevisiae)UniProtKB:P33317 DUT (human)UniProtKB:P33316 dut (Escherichia coli K-12)UniProtKB:P06968

Function

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

Removes dUTP (made from dUDP by NDP kinase) from the pool, preventing uracil misincorporation, and supplies dUMP.

dCMP deamination by dCMP deaminaseReactiondcmp_deaminase_route

Annotons

dCMP deaminase
dcmp_deaminase_activity
Participant: Family: dCMP deaminases
Family:
dCMP deaminasesPANTHER:PTHR11086:SF18
Representative Members: DCD1 (Saccharomyces cerevisiae)UniProtKB:P06773 DCTD (human)UniProtKB:P32321

Function

dCMP deaminase activityGO:0004132
Substrates: dCMP water
Products: dUMP ammonia

Converts dCMP (from dCTP turnover and deoxycytidine salvage) to dUMP; it is allosterically activated by dCTP and inhibited by dTTP, balancing dCTP against dTTP.

Part 2: thymidylate synthesis
dUMP + 5,10-methylene-THF to dTMP + dihydrofolateReactionthymidylate_synthase_step

Annotons

Thymidylate synthase
thymidylate_synthase_activity
Participant: Family: ThyA-type thymidylate synthases
Family:
ThyA-type thymidylate synthasesPANTHER:PTHR11548
Representative Members: CDC21 (Saccharomyces cerevisiae)UniProtKB:P06785 TYMS (human)UniProtKB:P04818 thyA (Escherichia coli K-12)UniProtKB:P0A884

Function

thymidylate synthase activityGO:0004799
Substrates: dUMP 5,10-methylenetetrahydrofolate
Products: dTMP 7,8-dihydrofolate

Locations

nuclear peripheryGO:0034399

Reductive methylation of dUMP; dihydrofolate is recycled by dihydrofolate reductase (tetrahydrofolate_biosynthesis / folate_one_carbon_interconversion). Target of 5-fluorouracil and antifolates.

Part 3: dTMP phosphorylation
dTMP + ATP to dTDP + ADPReactiondtmp_kinase_step

Annotons

Thymidylate kinase
dtmp_kinase_activity
Participant: Family: thymidylate kinases
Family:
thymidylate kinasesPANTHER:PTHR10344
Representative Members: CDC8 (Saccharomyces cerevisiae)UniProtKB:P00572 DTYMK (human)UniProtKB:P23919 tmk (Escherichia coli K-12)UniProtKB:P0A720

Function

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

The step common to de novo and salvage dTTP synthesis. CDC8 also phosphorylates dUMP weakly (RXN-14122 in YeastCyc).

Part 4: dTDP phosphorylation
dTDP + ATP to dTTP + ADPReactiondtdp_kinase_step

Annotons

Nucleoside-diphosphate kinase (dTDP to dTTP)
dtdp_ndp_kinase_activity
Participant: Family: nucleoside-diphosphate kinases (NDK/NME)
Family:
nucleoside-diphosphate kinases (NDK/NME)PANTHER:PTHR11349
Representative Members: YNK1 (Saccharomyces cerevisiae)UniProtKB:P36010 NME1 (human)UniProtKB:P15531

Function

nucleoside diphosphate kinase activityGO:0004550
Substrates: dTDP ATP
Products: dTTP ADP

Completes dTTP synthesis.