De novo UMP biosynthesis and conversion to UTP and CTP

The conserved six-reaction pathway that builds UMP from glutamine, hydrogencarbonate, ATP, aspartate, and PRPP, followed by phosphorylation of UMP to UTP and amination of UTP to CTP. Carbamoyl phosphate is formed first, followed by assembly and oxidation of the pyrimidine ring, attachment to phosphoribose, and decarboxylation to UMP. UMP kinase and nucleoside-diphosphate kinase then make UTP, and CTP synthase transfers the glutamine amide nitrogen to UTP to make CTP. Enzyme architecture varies: bacteria commonly use separate CarA, CarB, PyrB, PyrC, PyrE, and PyrF proteins, whereas animals fuse the first three activities in CAD and the final two activities in UMPS; fungi fuse the carbamoyl-phosphate synthetase and aspartate carbamoyltransferase in one protein that also carries an inactive dihydroorotase-like domain, and use separate dihydroorotase, orotate phosphoribosyltransferase and OMP decarboxylase proteins. These fusions do not change the chemical leaves represented by the module. Dihydroorotate oxidation has two implementations: membrane-associated quinone-dependent (class 2) enzymes, which in eukaryotes sit on the mitochondrial inner membrane and couple pyrimidine synthesis to respiration, and soluble fumarate-dependent (class 1A) enzymes, acquired by Saccharomyces yeasts from bacteria, which allow pyrimidine synthesis without oxygen. Bacteria phosphorylate UMP with a PyrH-type UMP kinase, eukaryotes with a UMP/CMP kinase of the adenylate kinase family.

MODULE:de_novo_pyrimidine_synthesisDRAFTMetabolic Pathwaymodules/de_novo_pyrimidine_synthesis.yaml
'de novo' UMP biosynthetic processGO:0044205 'de novo' CTP biosynthetic processGO:0044210
YeastPathways:PWY-5686-1
UMP biosynthesis I (S. cerevisiae, SGD YeastPathways)
Six reactions with URA2, URA4, URA1 (fumarate-dependent, RXN-9929), URA5/URA10 and URA3. The carbamoyl-phosphate synthase reaction also lists CPA1/CPA2, which form the arginine-specific enzyme and are not pyrimidine-pathway catalysts.
YeastPathways:PYRIMID-RNTSYN-PWY
de novo biosynthesis of pyrimidine ribonucleotides (S. cerevisiae, SGD YeastPathways)
UMP synthesis plus URA6, UDP kinase (no gene) and URA7/URA8. URA1 is drawn with the quinone-dependent DHODH reaction (EC 1.3.5.2) although the yeast enzyme uses fumarate (PMID:1409592).
YeastPathways:PWY0-162
superpathway of pyrimidine ribonucleotides de novo biosynthesis (S. cerevisiae, SGD YeastPathways)
Same reactions as PYRIMID-RNTSYN-PWY with the fumarate-dependent URA1 reaction.
YeastPathways:PWY-7176
UTP and CTP de novo biosynthesis (S. cerevisiae, SGD YeastPathways)
URA6, UDP kinase (no gene in YeastCyc; YNK1 in the GO-CAM) and URA7/URA8.
GO:0044205
'de novo' UMP biosynthetic process
Grounds the complete pathway from precursor metabolites to UMP.
GO:0044210
'de novo' CTP biosynthetic process
Grounds the downstream UMP-to-CTP extension.
file:PSEPK/carA/carA-uniprot.txt
PSEPK CarA UniProtKB record
Defines the glutaminase small-chain contribution to carbamoyl-phosphate synthesis and gives Q88DU5 as a bacterial exemplar.
file:PSEPK/carB/carB-uniprot.txt
PSEPK CarB UniProtKB record
Defines the ATP-dependent large-chain contribution to carbamoyl-phosphate synthesis and gives Q88DU6 as a bacterial exemplar.
file:PSEPK/pyrB/pyrB-uniprot.txt
PSEPK PyrB UniProtKB record
Defines the aspartate carbamoyltransferase reaction and gives Q88D30 as a bacterial exemplar.
file:PSEPK/pyrC/pyrC-uniprot.txt
PSEPK PyrC UniProtKB record
Defines the dihydroorotase reaction and gives Q88NW7 as a bacterial exemplar.
file:PSEPK/pyrD/pyrD-uniprot.txt
PSEPK PyrD UniProtKB record
Defines quinone-dependent dihydroorotate oxidation and gives Q88L40 as a bacterial exemplar.
file:PSEPK/pyrE/pyrE-uniprot.txt
PSEPK PyrE UniProtKB record
Defines orotate phosphoribosyltransferase chemistry and gives Q88C92 as a bacterial exemplar.
file:PSEPK/pyrF/pyrF-uniprot.txt
PSEPK PyrF UniProtKB record
Defines OMP decarboxylation and gives Q88LW2 as a bacterial exemplar.
PMID:7896697
Aspartate transcarbamoylase genes of Pseudomonas putida: requirement for an inactive dihydroorotase for assembly into the dodecameric holoenzyme.
Grounds the Pseudomonas PyrB/PyrC' dodecamer and establishes PyrC' as an inactive structural partner rather than the pathway dihydroorotase reaction.
file:projects/P_PUTIDA/deep-research/PSEPK__de_novo_pyrimidine_synthesis__ppu00240-deep-research-openscientist.md
OpenScientist species-aware review of de novo UMP biosynthesis in Pseudomonas putida KT2440
Confirms that the six reaction leaves are satisfiable by CarA/CarB, PyrB, PyrC, PyrD, PyrE, and PyrF; identifies PyrC' as a non-catalytic structural partner and the CarAB reaction as a cross-pathway dependency shared with arginine biosynthesis.
file:human/CAD/CAD-ai-review.yaml
Human CAD gene review
Grounds the fused eukaryotic architecture for the first three reaction leaves.
file:human/UMPS/UMPS-ai-review.yaml
Human UMPS gene review
Grounds the fused eukaryotic architecture for the final two reaction leaves.
file:yeast/URA2/URA2-ai-review.yaml
S. cerevisiae URA2 gene review
URA2 core functions are glutamine-dependent carbamoyl-phosphate synthase (GO:0004088) and aspartate carbamoyltransferase (GO:0004070) in the cytosol; its dihydroorotase-like domain is inactive.
file:yeast/CPA1/CPA1-ai-review.yaml
S. cerevisiae CPA1 gene review
CPA1 is the glutaminase subunit of the arginine-specific CPSase A (core process GO:0006526 arginine biosynthesis).
file:yeast/CPA2/CPA2-ai-review.yaml
S. cerevisiae CPA2 gene review
CPA2 is the synthetase subunit of the arginine-specific CPSase A.
PMID:2679804
Pyrimidine biosynthesis in Saccharomyces cerevisiae: the ura2 cluster gene, its multifunctional enzyme product, and other structural or regulatory genes involved in de novo UMP synthesis.
Six structural genes (URA2, URA4, URA1, URA5, URA10, URA3) make UMP; URA2 encodes the CPSase-ATCase multifunctional protein with a GATase, CPSase, inactive DHOase-like and ATCase domain.
PMID:2897615
Structure of the Saccharomyces cerevisiae URA4 gene encoding dihydroorotase.
URA4 encodes a monofunctional dihydroorotase related to the enterobacterial enzymes.
PMID:1409592
Divergent evolution of pyrimidine biosynthesis between anaerobic and aerobic yeasts.
S. cerevisiae DHODH (URA1) is cytosolic and uses fumarate as electron acceptor, whereas S. pombe DHODH is mitochondrial and requires the respiratory chain.
PMID:15014982
Horizontal gene transfer promoted evolution of the ability to propagate under anaerobic conditions in yeasts.
The cytoplasmic Saccharomyces DHODH is related to Lactococcus lactis DHODase and was acquired by horizontal transfer; only it supports anaerobic growth.
PMID:8391780
Characteristics, substrate analysis, and intracellular location of Saccharomyces cerevisiae UMP kinase.
URA6 UMP kinase phosphorylates UMP and dUMP and is cytoplasmic and nuclear, not mitochondrial.
PMID:1333436
The adenylate kinase family in yeast: identification of URA6 as a multicopy suppressor of deficiency in major AMP kinase.
URA6 is an adenylate-kinase-family nucleoside monophosphate kinase that also phosphorylates CMP.
PMID:8121398
Use of synthetic lethal mutants to clone and characterize a novel CTP synthetase gene in Saccharomyces cerevisiae.
URA7 and URA8 both encode CTP synthetase; the double null is lethal and URA7 is the major gene.
PMID:7559626
Differential biochemical regulation of the URA7- and URA8-encoded CTP synthetases from Saccharomyces cerevisiae.
URA8-encoded CTP synthetase was purified from the cytosolic fraction.
PMID:9858611
Activation of transcription by metabolic intermediates of the pyrimidine biosynthetic pathway.
Ppr1p senses dihydroorotate and orotate and activates later pathway genes (regulation, outside module core).
15Nodes
10Parts
2Variant Sets
4Variants
12Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:de_novo_pyrimidine_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

33 gene-function check(s) reflected in core functions · 0 conflict(s) · 15 evidence or coverage gap(s) (55 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
carbamoyl_phosphate_glutaminase_component carA (Pseudomonas putida KT2440)
UniProtKB:Q88DU5
Family Representative
glutaminase activity
GO:0004359
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
carbamoyl_phosphate_glutaminase_component CAD (human)
UniProtKB:P27708
Family Representative
glutaminase activity
GO:0004359
Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
carbamoyl_phosphate_glutaminase_component URA2 (Saccharomyces cerevisiae)
UniProtKB:P07259
Family Representative
glutaminase activity
GO:0004359
Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
carbamoyl_phosphate_glutaminase_component ura1 (Schizosaccharomyces pombe)
UniProtKB:Q09794
Family Representative
glutaminase activity
GO:0004359
Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
carbamoyl_phosphate_synthetase_component carB (Pseudomonas putida KT2440)
UniProtKB:Q88DU6
Family Representative
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
GO:0004088
Contributes Only
The review records contribution to this activity, not independent enabling. Check whether the module participant should be a complex.
carbamoyl_phosphate_synthetase_component CAD (human)
UniProtKB:P27708
Family Representative
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
GO:0004088
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
carbamoyl_phosphate_synthetase_component URA2 (Saccharomyces cerevisiae)
UniProtKB:P07259
Family Representative
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
GO:0004088
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
carbamoyl_phosphate_synthetase_component ura1 (Schizosaccharomyces pombe)
UniProtKB:Q09794
Family Representative
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
GO:0004088
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aspartate_carbamoyltransferase_activity pyrB (Pseudomonas putida KT2440)
UniProtKB:Q88D30
Family Representative
aspartate carbamoyltransferase activity
GO:0004070
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aspartate_carbamoyltransferase_activity CAD (human)
UniProtKB:P27708
Family Representative
aspartate carbamoyltransferase activity
GO:0004070
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aspartate_carbamoyltransferase_activity URA2 (Saccharomyces cerevisiae)
UniProtKB:P07259
Family Representative
aspartate carbamoyltransferase activity
GO:0004070
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
aspartate_carbamoyltransferase_activity ura1 (Schizosaccharomyces pombe)
UniProtKB:Q09794
Family Representative
aspartate carbamoyltransferase activity
GO:0004070
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotase_activity pyrC (Pseudomonas putida KT2440)
UniProtKB:Q88NW7
Family Representative
dihydroorotase activity
GO:0004151
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotase_activity CAD (human)
UniProtKB:P27708
Family Representative
dihydroorotase activity
GO:0004151
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotase_activity URA4 (Saccharomyces cerevisiae)
UniProtKB:P20051
Family Representative
dihydroorotase activity
GO:0004151
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotase_activity ura2 (Schizosaccharomyces pombe)
UniProtKB:Q9UTI0
Family Representative
dihydroorotase activity
GO:0004151
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotate_dehydrogenase_activity pyrD (Pseudomonas putida KT2440)
UniProtKB:Q88L40
Family Representative
dihydroorotate dehydrogenase (quinone) activity
GO:0106430
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotate_dehydrogenase_activity DHODH (human)
UniProtKB:Q02127
Family Representative
dihydroorotate dehydrogenase (quinone) activity
GO:0106430
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotate_dehydrogenase_activity ura3 (Schizosaccharomyces pombe)
UniProtKB:P32747
Family Representative
dihydroorotate dehydrogenase (quinone) activity
GO:0106430
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dihydroorotate_dehydrogenase_fumarate_activity URA1 (Saccharomyces cerevisiae)
UniProtKB:P28272
Family Representative
dihydroorotate dehydrogenase (fumarate) activity
GO:1990663
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
orotate_phosphoribosyltransferase_activity pyrE (Pseudomonas putida KT2440)
UniProtKB:Q88C92
Family Representative
orotate phosphoribosyltransferase activity
GO:0004588
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
orotate_phosphoribosyltransferase_activity UMPS (human)
UniProtKB:P11172
Family Representative
orotate phosphoribosyltransferase activity
GO:0004588
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
orotate_phosphoribosyltransferase_activity URA5 (Saccharomyces cerevisiae)
UniProtKB:P13298
Family Representative
orotate phosphoribosyltransferase activity
GO:0004588
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
orotate_phosphoribosyltransferase_activity URA10 (Saccharomyces cerevisiae)
UniProtKB:P30402
Family Representative
orotate phosphoribosyltransferase activity
GO:0004588
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
orotate_phosphoribosyltransferase_activity ura5 (Schizosaccharomyces pombe)
UniProtKB:O94331
Family Representative
orotate phosphoribosyltransferase activity
GO:0004588
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
omp_decarboxylase_activity pyrF (Pseudomonas putida KT2440)
UniProtKB:Q88LW2
Family Representative
orotidine-5'-phosphate decarboxylase activity
GO:0004590
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
omp_decarboxylase_activity UMPS (human)
UniProtKB:P11172
Family Representative
orotidine-5'-phosphate decarboxylase activity
GO:0004590
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
omp_decarboxylase_activity URA3 (Saccharomyces cerevisiae)
UniProtKB:P03962
Family Representative
orotidine-5'-phosphate decarboxylase activity
GO:0004590
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
omp_decarboxylase_activity ura4 (Schizosaccharomyces pombe)
UniProtKB:P14965
Family Representative
orotidine-5'-phosphate decarboxylase activity
GO:0004590
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
eukaryotic_ump_kinase_activity URA6 (Saccharomyces cerevisiae)
UniProtKB:P15700
Family Representative
UMP kinase activity
GO:0033862
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
eukaryotic_ump_kinase_activity ura6 (Schizosaccharomyces pombe)
UniProtKB:O59771
Family Representative
UMP kinase activity
GO:0033862
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
eukaryotic_ump_kinase_activity CMPK1 (human)
UniProtKB:P30085
Family Representative
UMP kinase activity
GO:0033862
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
pyrH_ump_kinase_activity pyrH (Escherichia coli K-12)
UniProtKB:P0A7E9
Family Representative
UMP kinase activity
GO:0033862
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
udp_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).
udp_ndp_kinase_activity ndk1 (Schizosaccharomyces pombe)
UniProtKB:P49740
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).
udp_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.
ctp_synthase_activity URA7 (Saccharomyces cerevisiae)
UniProtKB:P28274
Family Representative
CTP synthase activity
GO:0003883
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctp_synthase_activity URA8 (Saccharomyces cerevisiae)
UniProtKB:P38627
Family Representative
CTP synthase activity
GO:0003883
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctp_synthase_activity ura7 (Schizosaccharomyces pombe)
UniProtKB:O42644
Family Representative
CTP synthase activity
GO:0003883
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctp_synthase_activity CTPS1 (human)
UniProtKB:P17812
Family Representative
CTP synthase activity
GO:0003883
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctp_synthase_activity pyrG (Escherichia coli K-12)
UniProtKB:P0A7E5
Family Representative
CTP synthase activity
GO:0003883
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
carbamoyl_phosphate_glutaminase_component carbamoyl-phosphate synthase small-chain domain family
InterPro:IPR006274
Family
glutaminase activity
GO:0004359
Family Review Missing
No supported structured family review is available for InterPro:IPR006274.
carbamoyl_phosphate_synthetase_component carbamoyl-phosphate synthase large-chain domain family
InterPro:IPR006275
Family
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activity
GO:0004088
Family Review Missing
No supported structured family review is available for InterPro:IPR006275.
aspartate_carbamoyltransferase_activity aspartate carbamoyltransferase domain family
InterPro:IPR002082
Family
aspartate carbamoyltransferase activity
GO:0004070
Family Review Missing
No supported structured family review is available for InterPro:IPR002082.
dihydroorotase_activity dihydroorotase catalytic domain family
InterPro:IPR002195
Family
dihydroorotase activity
GO:0004151
Family Review Missing
No supported structured family review is available for InterPro:IPR002195.
dihydroorotate_dehydrogenase_activity class 2 dihydroorotate dehydrogenase family
PANTHER:PTHR48109:SF4
Family
dihydroorotate dehydrogenase (quinone) activity
GO:0106430
Family Supported
Family review supports GO:0106430 for PANTHER:PTHR48109:SF4. Class 2 only. This is the function of the module's quinone_dhodh_variant, which uses the base family id with GO:0106430 as required function. That restriction is needed because the base family also contains the soluble class 1 enzymes. S. pombe ura3 activity depends on an intact respiratory chain, which fits a quinone acceptor.
dihydroorotate_dehydrogenase_fumarate_activity class 1A (fumarate) dihydroorotate dehydrogenases
PANTHER:PTHR48109:SF1
Family
dihydroorotate dehydrogenase (fumarate) activity
GO:1990663
Family Supported
Family review supports GO:1990663 for PANTHER:PTHR48109:SF1. Only class 1A members of SF1, such as S. cerevisiae URA1 and Lactococcus PyrDA. This is the function of the module's fumarate_dhodh_variant, which selects SF1 with no required_function. SF1 also holds 93 reviewed class 1B NAD(+)-type PyrDB catalytic subunits, so an SF1 selector on its own over-includes. See the member exception.
orotate_phosphoribosyltransferase_activity orotate phosphoribosyltransferase domain family
InterPro:IPR023031
Family
orotate phosphoribosyltransferase activity
GO:0004588
Family Review Missing
No supported structured family review is available for InterPro:IPR023031.
omp_decarboxylase_activity OMP decarboxylase domain family
InterPro:IPR014732
Family
orotidine-5'-phosphate decarboxylase activity
GO:0004590
Family Review Missing
No supported structured family review is available for InterPro:IPR014732.
eukaryotic_ump_kinase_activity eukaryotic UMP/CMP kinases
PANTHER:PTHR23359:SF206
Family
UMP kinase activity
GO:0033862
Family Supported
Family review supports GO:0033862 for PANTHER:PTHR23359:SF206. Eukaryotic UMP/CMP kinases only. PAINT places the term at PTN000599579 (Eukaryota), whose recipients include URA6, S. pombe ura6, CMPK1 and Arabidopsis UMK1, UMK2 and UMK3. This is the module's function for eukaryotic_ump_kinase_activity, which selects the three subfamilies listed here with representatives URA6, ura6 and CMPK1. The annoton has no required_function, so it is the subfamily list that keeps the selector off the adenylate kinases; a base-family selector would take in every adenylate kinase. SF206 also holds the bacterial adenylate kinases, which do not inherit the term (see the member exception); bacteria make UDP with PyrH (PTHR42833). Human AK9 (SF148) also inherits from PTN000599579 but was not assessed here.
eukaryotic_ump_kinase_activity eukaryotic UMP/CMP kinases
PANTHER:PTHR23359:SF171
Family
UMP kinase activity
GO:0033862
Family Supported
Family review supports GO:0033862 for PANTHER:PTHR23359:SF171. Eukaryotic UMP/CMP kinases only. PAINT places the term at PTN000599579 (Eukaryota), whose recipients include URA6, S. pombe ura6, CMPK1 and Arabidopsis UMK1, UMK2 and UMK3. This is the module's function for eukaryotic_ump_kinase_activity, which selects the three subfamilies listed here with representatives URA6, ura6 and CMPK1. The annoton has no required_function, so it is the subfamily list that keeps the selector off the adenylate kinases; a base-family selector would take in every adenylate kinase. SF206 also holds the bacterial adenylate kinases, which do not inherit the term (see the member exception); bacteria make UDP with PyrH (PTHR42833). Human AK9 (SF148) also inherits from PTN000599579 but was not assessed here.
eukaryotic_ump_kinase_activity eukaryotic UMP/CMP kinases
PANTHER:PTHR23359:SF246
Family
UMP kinase activity
GO:0033862
Family Supported
Family review supports GO:0033862 for PANTHER:PTHR23359:SF246. Eukaryotic UMP/CMP kinases only. PAINT places the term at PTN000599579 (Eukaryota), whose recipients include URA6, S. pombe ura6, CMPK1 and Arabidopsis UMK1, UMK2 and UMK3. This is the module's function for eukaryotic_ump_kinase_activity, which selects the three subfamilies listed here with representatives URA6, ura6 and CMPK1. The annoton has no required_function, so it is the subfamily list that keeps the selector off the adenylate kinases; a base-family selector would take in every adenylate kinase. SF206 also holds the bacterial adenylate kinases, which do not inherit the term (see the member exception); bacteria make UDP with PyrH (PTHR42833). Human AK9 (SF148) also inherits from PTN000599579 but was not assessed here.
pyrH_ump_kinase_activity PyrH-type UMP kinases
PANTHER:PTHR42833
Family
UMP kinase activity
GO:0033862
Family Supported
Family review supports GO:0033862 FAMILY_WIDE. This is the module's function for the bacterial PyrH variant. It holds for the bacterial and plastid members. The MosB caveat is in the coherence reason; MosB is not a PAINT recipient.
udp_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.
ctp_synthase_activity CTP synthases (PyrG/CTPS/URA7)
PANTHER:PTHR11550
Family
CTP synthase activity
GO:0003883
Family Supported
Family review supports GO:0003883 FAMILY_WIDE. This is the module's function for ctp_synthase_activity. It holds for all members, and the two yeast isozymes overlap in function.

Gene-review completeness (29/33 grounded genes reviewed)

25 complete review(s) · 19 with deep research · 4 missing review · 10 reviewed but lacking deep research

Gene Review Complete Deep research
CAD P27708 ✓ 70/84 ✗
carA Q88DU5 ✓ ✓ ✓
carB Q88DU6 ✓ ✓ ✓
CTPS1 P17812 ✓ 53/54 ✗
DHODH Q02127 ✓ 25/26 ✓
ndk1 P49740 ✓ ✓ ✗
pyrG (Escherichia coli K-12) P0A7E5 ✗ — —
pyrH (Escherichia coli K-12) P0A7E9 ✗ — —
NME1 (human) P15531 ✗ — —
CMPK1 (human) P30085 ✗ — —
pyrB Q88D30 ✓ ✓ ✓
pyrC Q88NW7 ✓ ✓ ✓
pyrD Q88L40 ✓ ✓ ✓
pyrE Q88C92 ✓ ✓ ✓
pyrF Q88LW2 ✓ ✓ ✓
UMPS P11172 ✓ ✓ ✗
URA1 P28272 ✓ ✓ ✓
ura1 Q09794 ✓ ✓ ✗
URA10 P30402 ✓ ✓ ✓
URA2 P07259 ✓ ✓ ✓
ura2 Q9UTI0 ✓ ✓ ✗
URA3 P03962 ✓ ✓ ✓
ura3 P32747 ✓ ✓ ✗
ura4 P14965 ✓ ✓ ✗
URA4 P20051 ✓ ✓ ✓
ura5 O94331 ✓ ✓ ✗
URA5 P13298 ✓ ✓ ✓
ura6 O59771 ✓ ✓ ✗
URA6 P15700 ✓ ✓ ✓
ura7 O42644 ✓ ✓ ✓
URA7 P28274 ✓ ✓ ✓
URA8 P38627 ✓ 29/30 ✓
YNK1 P36010 ✓ ✓ ✓

Details

De novo UMP biosynthesis and conversion to UTP and CTPMetabolic Pathwayde_novo_pyrimidine_synthesis
'de novo' UMP biosynthetic processGO:0044205 'de novo' CTP biosynthetic processGO:0044210

ALIGN with the YeastPathways crosswalk (PWY-5686-1, PYRIMID-RNTSYN-PWY, PWY0-162, PWY-7176). The six chemical leaves are conserved despite taxon-specific protein architecture: bacteria commonly use separate CarA/CarB/PyrB/PyrC/PyrE/PyrF chains, animals fuse the first three activities in CAD and the last two in UMPS, and fungi use a CPSase-ATCase fusion (S. cerevisiae URA2, S. pombe ura1) whose dihydroorotase-like domain is inactive (PMID:2679804), plus separate URA4/ura2 dihydroorotase, URA5+URA10/ura5 OPRTase and URA3/ura4 ODCase. Fungal gene names are not orthologous between the two yeasts (S. cerevisiae URA1 = DHODH but S. pombe ura1 = CPSase-ATCase). Dihydroorotate oxidation is modelled as two variants: class 2 quinone DHODH (bacteria, animals, S. pombe ura3 in mitochondria) and the class 1A fumarate DHODH of S. cerevisiae URA1, which is cytosolic and of bacterial origin (PMID:1409592, PMID:15014982). The UMP to UTP and CTP steps (URA6, YNK1, URA7/URA8) were added as part 7 per the crosswalk; bacterial PyrH and eukaryotic UMP/CMP kinases are unrelated families and are modelled as variants. YeastCyc corrections: CPA1/CPA2 are listed for CARBPSYN-RXN in PWY-5686-1 but form the arginine-specific CPSase A (committed CPA1/CPA2 reviews) and are not exemplars here, although CPSase A carbamoyl phosphate can partly reach the pyrimidine pathway; PYRIMID-RNTSYN-PWY draws URA1 with the quinone-dependent reaction (EC 1.3.5.2) instead of the fumarate reaction; UDP kinase has no gene in YeastCyc (YNK1 added, as in the GO-CAM). GO-CAM disagreements: YeastPathways_PYRIMID-RNTSYN-PWY gives URA1 the generic GO:0004152 with no location, URA6 the obsolete GO:0004127 in several models, and labels the pathway GO:0006207 'de novo' pyrimidine nucleobase biosynthetic process although its products are nucleotides. The PomBase model 69a0c46f00003691 (listed in the crosswalk under pyrimidine_salvage) supplies the S. pombe exemplars. Carbamoyl phosphate also feeds arginine biosynthesis, so pathway assignment of bacterial CarA/CarB requires process context rather than reaction identity alone; pyrimidine CPS II must not be conflated with mitochondrial urea-cycle CPS1. PRPP supply (pentose_phosphate_pathway) is upstream and pyrimidine salvage (pyrimidine_salvage) and deoxynucleotide synthesis (dntp_de_novo_synthesis) are separate modules. Regulation (outside the core): UTP feedback-inhibits URA2 CPSase and Ppr1p senses dihydroorotate and orotate to activate later URA genes (PMID:9858611). Human disease and drug examples remain useful context: UMPS deficiency causes hereditary orotic aciduria, DHODH deficiency causes Miller syndrome, CAD deficiency causes a uridine-responsive developmental epileptic encephalopathy, and DHODH is targeted by leflunomide/teriflunomide. Pseudomonas PyrC' is a lineage-specific inactive dihydroorotase-like structural partner of PyrB and is not an additional dihydroorotase reaction leaf.

Connections

Carbamoyl phosphate is consumed by aspartate carbamoyltransferase.
N-carbamoyl-L-aspartate undergoes ring closure.
Dihydroorotate is oxidized to orotate.
Orotate receives a phosphoribosyl group from PRPP.
OMP is decarboxylated to UMP.
omp_decarboxylation -> ump_to_ctp Provides Input For
UMP is phosphorylated to UDP and UTP and aminated to CTP.
Part 1: glutamine-dependent carbamoyl-phosphate synthesis
Glutamine and hydrogencarbonate to carbamoyl phosphateReactioncarbamoyl_phosphate_synthesis

The glutaminase and ATP-dependent synthetase domains occur in separate CarA and CarB chains in many bacteria, in one CAD polypeptide in animals and in the CPSase-ATCase protein of fungi (URA2 / S. pombe ura1). Fungi have a second, arginine-specific carbamoyl-phosphate synthetase (CPA1/CPA2) that is not part of this module.

Annotons

Carbamoyl-phosphate synthase glutaminase component
carbamoyl_phosphate_glutaminase_component
Participant: Family: carbamoyl-phosphate synthase small-chain domain family
Family:
carbamoyl-phosphate synthase small-chain domain familyInterPro:IPR006274
Representative Members: carA (Pseudomonas putida KT2440)UniProtKB:Q88DU5 CAD (human)UniProtKB:P27708 URA2 (Saccharomyces cerevisiae)UniProtKB:P07259 ura1 (Schizosaccharomyces pombe)UniProtKB:Q09794
Required Function:
glutaminase activityGO:0004359

Function

glutaminase activityGO:0004359
Substrates: L-glutamine water
Products: L-glutamate ammonia channeled to the synthetase component

Processes

'de novo' UMP biosynthetic processGO:0044205

Supplies ammonia to the coupled carbamoyl-phosphate synthetase domain.

Carbamoyl-phosphate synthase ATP-dependent component
carbamoyl_phosphate_synthetase_component
Participant: Family: carbamoyl-phosphate synthase large-chain domain family
Family:
carbamoyl-phosphate synthase large-chain domain familyInterPro:IPR006275
Representative Members: carB (Pseudomonas putida KT2440)UniProtKB:Q88DU6 CAD (human)UniProtKB:P27708 URA2 (Saccharomyces cerevisiae)UniProtKB:P07259 ura1 (Schizosaccharomyces pombe)UniProtKB:Q09794
Required Function:
carbamoyl-phosphate synthase (glutamine-hydrolyzing) activityGO:0004088

Function

carbamoyl-phosphate synthase (glutamine-hydrolyzing) activityGO:0004088
Substrates: hydrogencarbonate L-glutamine ATP water
Products: carbamoyl phosphate L-glutamate ADP phosphate proton

Processes

'de novo' UMP biosynthetic processGO:0044205

Uses channeled ammonia, hydrogencarbonate, and ATP to form carbamoyl phosphate.

Part 2: aspartate carbamoylation
Carbamoyl phosphate and aspartate to carbamoyl aspartateReactionaspartate_carbamoylation

Annotons

Aspartate carbamoyltransferase activity
aspartate_carbamoyltransferase_activity
Participant: Family: aspartate carbamoyltransferase domain family
Family:
aspartate carbamoyltransferase domain familyInterPro:IPR002082
Representative Members: pyrB (Pseudomonas putida KT2440)UniProtKB:Q88D30 CAD (human)UniProtKB:P27708 URA2 (Saccharomyces cerevisiae)UniProtKB:P07259 ura1 (Schizosaccharomyces pombe)UniProtKB:Q09794
Required Function:
aspartate carbamoyltransferase activityGO:0004070

Function

aspartate carbamoyltransferase activityGO:0004070
Substrates: carbamoyl phosphate L-aspartate
Products: N-carbamoyl-L-aspartate phosphate

Processes

'de novo' UMP biosynthetic processGO:0044205

Builds the first carbon-nitrogen framework of the pyrimidine ring. In P. putida, catalytic PyrB chains assemble with inactive PyrC' pseudoenzyme chains rather than PyrI regulatory subunits.

Part 3: dihydroorotate ring closure
Carbamoyl aspartate to dihydroorotateReactiondihydroorotate_ring_closure

Annotons

Dihydroorotase activity
dihydroorotase_activity
Participant: Family: dihydroorotase catalytic domain family
Family:
dihydroorotase catalytic domain familyInterPro:IPR002195
Representative Members: pyrC (Pseudomonas putida KT2440)UniProtKB:Q88NW7 CAD (human)UniProtKB:P27708 URA4 (Saccharomyces cerevisiae)UniProtKB:P20051 ura2 (Schizosaccharomyces pombe)UniProtKB:Q9UTI0
Required Function:
dihydroorotase activityGO:0004151

Function

dihydroorotase activityGO:0004151
Substrates: N-carbamoyl-L-aspartate
Products: (S)-dihydroorotate water

Processes

'de novo' UMP biosynthetic processGO:0044205

Closes the pyrimidine ring to form dihydroorotate. The dihydroorotase-like domain of fungal URA2 is catalytically inactive (PMID:2679804), so fungi need the separate URA4 enzyme.

Part 4: dihydroorotate oxidation
Dihydroorotate to orotateReactiondihydroorotate_oxidation
Variant set: DHODH electron acceptor and compartment by electron acceptor (quinone versus fumarate) and compartment (One Or More)

Some yeasts (for example Lachancea kluyveri) carry both types (PMID:15014982). Class 1B NAD-dependent PyrDB-PyrK enzymes of some bacteria are not modelled.

Class 2 quinone-dependent DHODH (membrane-associated)Reactionquinone_dhodh_variant

Annotons

Quinone-dependent dihydroorotate dehydrogenase activity
dihydroorotate_dehydrogenase_activity
Participant: Family: class 2 dihydroorotate dehydrogenase family
Family:
class 2 dihydroorotate dehydrogenase family
Representative Members: pyrD (Pseudomonas putida KT2440)UniProtKB:Q88L40 DHODH (human)UniProtKB:Q02127 ura3 (Schizosaccharomyces pombe)UniProtKB:P32747
Required Function:
dihydroorotate dehydrogenase (quinone) activityGO:0106430

Function

dihydroorotate dehydrogenase (quinone) activityGO:0106430
Substrates: (S)-dihydroorotate quinone
Products: orotate quinol

Processes

'de novo' UMP biosynthetic processGO:0044205

Oxidizes dihydroorotate to orotate. Class-2 enzymes are membrane-associated: bacterial PyrD acts peripherally at the plasma membrane, whereas animal and most fungal DHODHs are anchored to the mitochondrial inner membrane and pass electrons to ubiquinone, making pyrimidine synthesis respiration-dependent.

Class 1A fumarate-dependent DHODH (cytosolic)Reactionfumarate_dhodh_variant

Annotons

Fumarate-dependent dihydroorotate dehydrogenase activity
dihydroorotate_dehydrogenase_fumarate_activity
Participant: Family: class 1A (fumarate) dihydroorotate dehydrogenases
Family:
class 1A (fumarate) dihydroorotate dehydrogenasesPANTHER:PTHR48109:SF1
Representative Members: URA1 (Saccharomyces cerevisiae)UniProtKB:P28272

Function

dihydroorotate dehydrogenase (fumarate) activityGO:1990663
Substrates: (S)-dihydroorotate fumarate
Products: orotate succinate

Processes

'de novo' UMP biosynthetic processGO:0044205

Locations

cytosolGO:0005829

Soluble FMN enzyme that uses fumarate instead of quinone, making pyrimidine synthesis independent of oxygen and the respiratory chain; it allows anaerobic growth of Saccharomyces yeasts (PMID:15014982).

Part 5: phosphoribosylation of orotate
Orotate and PRPP to OMPReactionorotate_phosphoribosylation

Annotons

Orotate phosphoribosyltransferase activity
orotate_phosphoribosyltransferase_activity
Participant: Family: orotate phosphoribosyltransferase domain family
Family:
orotate phosphoribosyltransferase domain familyInterPro:IPR023031
Representative Members: pyrE (Pseudomonas putida KT2440)UniProtKB:Q88C92 UMPS (human)UniProtKB:P11172 URA5 (Saccharomyces cerevisiae)UniProtKB:P13298 URA10 (Saccharomyces cerevisiae)UniProtKB:P30402 ura5 (Schizosaccharomyces pombe)UniProtKB:O94331
Required Function:
orotate phosphoribosyltransferase activityGO:0004588

Function

orotate phosphoribosyltransferase activityGO:0004588
Substrates: orotate 5-phospho-alpha-D-ribose 1-diphosphate
Products: orotidine 5'-phosphate diphosphate

Processes

'de novo' UMP biosynthetic processGO:0044205

Attaches the completed pyrimidine ring to phosphoribose.

Part 6: UMP formation by OMP decarboxylation
OMP to UMPReactionomp_decarboxylation

Annotons

Orotidine-5'-phosphate decarboxylase activity
omp_decarboxylase_activity
Participant: Family: OMP decarboxylase domain family
Family:
OMP decarboxylase domain familyInterPro:IPR014732
Representative Members: pyrF (Pseudomonas putida KT2440)UniProtKB:Q88LW2 UMPS (human)UniProtKB:P11172 URA3 (Saccharomyces cerevisiae)UniProtKB:P03962 ura4 (Schizosaccharomyces pombe)UniProtKB:P14965
Required Function:
orotidine-5'-phosphate decarboxylase activityGO:0004590

Function

orotidine-5'-phosphate decarboxylase activityGO:0004590
Substrates: orotidine 5'-phosphate proton
Products: UMP carbon dioxide

Processes

'de novo' UMP biosynthetic processGO:0044205

Produces UMP, completing the de novo UMP pathway.

Part 7: conversion of UMP to UTP and CTP
UMP to UDP, UTP and CTPMetabolic Pathwayump_to_ctp

Downstream extension shared with pyrimidine salvage: UMP kinase, nucleoside-diphosphate kinase and CTP synthase. The UDP made here is also the ribonucleotide reductase substrate for dUTP/dTTP synthesis (dntp_de_novo_synthesis).

Connections

Part 1: UMP phosphorylation
UMP + ATP to UDP + ADPReactionump_kinase_step
Variant set: UMP kinase families by enzyme family (lineage) (Exactly One)
Eukaryotic UMP/CMP kinase (adenylate kinase family)Reactioneukaryotic_ump_cmp_kinase_variant

Annotons

UMP/CMP kinase (URA6/CMPK1)
eukaryotic_ump_kinase_activity
Participant: Family: eukaryotic UMP/CMP kinases
Family:
eukaryotic UMP/CMP kinases Only the UMP-CMP kinase subfamilies (SF206, SF171, SF246) of PTHR23359 are selected; the broad nucleoside-monophosphate kinase family also contains adenylate kinases. SF206 also holds bacterial adenylate kinases, which the leaf function (UMP kinase activity) excludes.
Representative Members: URA6 (Saccharomyces cerevisiae)UniProtKB:P15700 ura6 (Schizosaccharomyces pombe)UniProtKB:O59771 CMPK1 (human)UniProtKB:P30085

Function

UMP kinase activityGO:0033862
Substrates: UMP ATP
Products: UDP ADP

Locations

cytosolGO:0005829

Also phosphorylates CMP and dCMP (salvage) and dUMP; the same protein serves pyrimidine_salvage.

Bacterial PyrH UMP kinase (amino-acid kinase family)Reactionbacterial_pyrH_variant

Annotons

UMP kinase (PyrH)
pyrH_ump_kinase_activity
Participant: Family: PyrH-type UMP kinases
Family:
PyrH-type UMP kinasesPANTHER:PTHR42833
Representative Members: pyrH (Escherichia coli K-12)UniProtKB:P0A7E9

Function

UMP kinase activityGO:0033862
Substrates: UMP ATP
Products: UDP ADP

Unrelated hexameric UMP kinase of bacteria and archaea (convergent with the eukaryotic enzyme).

Part 2: UDP phosphorylation
UDP + ATP to UTP + ADPReactionudp_kinase_step

Annotons

Nucleoside-diphosphate kinase (UDP to UTP)
udp_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 ndk1 (Schizosaccharomyces pombe)UniProtKB:P49740 NME1 (human)UniProtKB:P15531

Function

nucleoside diphosphate kinase activityGO:0004550
Substrates: UDP ATP
Products: UTP ADP

Broad-specificity terminal phosphorylation of UDP.

Part 3: UTP amination
UTP + L-glutamine + ATP to CTPReactionctp_synthase_step

Annotons

CTP synthase
ctp_synthase_activity
Participant: Family: CTP synthases (PyrG/CTPS/URA7)
Family:
CTP synthases (PyrG/CTPS/URA7)PANTHER:PTHR11550
Representative Members: URA7 (Saccharomyces cerevisiae)UniProtKB:P28274 URA8 (Saccharomyces cerevisiae)UniProtKB:P38627 ura7 (Schizosaccharomyces pombe)UniProtKB:O42644 CTPS1 (human)UniProtKB:P17812 pyrG (Escherichia coli K-12)UniProtKB:P0A7E5

Function

CTP synthase activityGO:0003883
Substrates: UTP L-glutamine ATP water
Products: CTP L-glutamate ADP phosphate

Locations

cytosolGO:0005829

The only de novo source of CTP; CTP is required for RNA, CDP-diacylglycerol phospholipid synthesis and dCTP formation. The enzyme forms filaments in many species.