Pyrimidine metabolism (WP4022)

Pyrimidines are nucleic acids and the products of pyrimidine degradation are water-soluble. The pyrimidine ring is synthesized before it is conjugated to PRPP. The first reaction is the conjugation of carbamoyl phosphate and aspartate to make N-carbamoylaspartate. The carbamoyl phosphate synthetase used in pyrimidine biosynthesis is located in the cytoplasm. The enzyme that carries out the reaction is aspartate transcarbamoylase, an enzyme that is closely regulated. The second reaction is ring closure to form dihydroorotic acid by the enzyme dihydroorotase. This circular product contains a 6-membered ring with nitrogen and carbons located in the same positions as in the mature pyrimidine ring. The third reaction is the oxidation of the ring to form a carbon- carbon bond. The reducing equivalents are transferred to a flavin cofactor of the enzyme dihydroorotate dehydrogenase. The product is orotic acid. Fourth, the orotate ring is transferred to phosphoribosyl pyrophosphate (PRPP) to form a 5-ribose-phosphate, orotidylic acid. Finally orotidylate is decarboxylated to yield UMP, which of course contains one of the bases of RNA. Cellular kinases convert UMP to UTP. Transfer of an amido nitrogen from glutamine by CTP synthetase converts UTP to CTP; this reaction uses an ATP high-energy phosphate. Pyrimidine synthesis is controlled at the first committed step. ATP stimulates the aspartate transcarbamoylase reaction, while CTP inhibits it. CTP is a feedback inhibitor of the pathway, and ATP is a feed-forward activator. This regulation ensures that a balanced supply of purines and pyrimidines exists for RNA and synthesis. Eukaryotic organisms contain a multifunctional enzyme with carbamoylphosphate synthetase, aspartate transcarbamoylase, and dihydroorotase activities. Two mechanisms control this enzyme. First, control at the level of enzyme synthesis exists; the transcription of the gene for the enzyme is reduced if an excess of pyrimidines is present. Secondly, control exists at the level of feedback inhibition by pyrimidine nucleotides. This enzyme is also an example of the phenomenon of metabolic channeling: aspartate, ammonia, and carbon dioxide enter the enzyme and come out as orotic acid Description text is based on [https://www.cliffsnotes.com/study-guides/biology/biochemistry-ii/purines-and-pyrimidines/pyrimidine-metabolism Cliff's Notes]. Pathway is based on [https://www.genome.jp/dbget-bin/www_bget?pathway+map00240 KEGG] Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4022 CPTAC Assay Portal]
last edited

Authors

Annahoekstra1, DeSl, Khanspers, MaintBot, Finterly, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: pyrimidine metabolic pathway

Participants

Label Type Compact Identifier
AK9 GeneProduct NCBI Protein
NUDT2 GeneProduct NCBI Protein
PNPT1 GeneProduct NCBI Protein
UppppU Metabolite KEGG Compound
beta-Alanine metabolism Pathway None
Alanine, aspartate and glutamate metabolism Pathway None
Pentose phosphate pathway Pathway None
Arginine and proline metabolism Pathway None
UDP Metabolite KEGG Compound
2-deoxy-D-ribose-1P Metabolite PubChem-compound
CDA GeneProduct Entrez Gene
DNA Metabolite KEGG Compound
dTTP Metabolite KEGG Compound
dCMP Metabolite KEGG Compound
DPYS GeneProduct Entrez Gene
UDP Metabolite KEGG Compound
TYMS GeneProduct Entrez Gene
TK2 GeneProduct Entrez Gene
CMP Metabolite HMDB
CAD GeneProduct Entrez Gene
N-Carbamoylaspartate Metabolite HMDB
CTPS1 GeneProduct Entrez Gene
dUTP Metabolite KEGG Compound
Cytidine Metabolite HMDB
PRPP Metabolite KEGG Compound
DPYD GeneProduct Entrez Gene
Dihydroorotate Metabolite HMDB
beta-Alanine Metabolite HMDB
ENTPD8 GeneProduct NCBI Protein
CTP Metabolite KEGG Compound
RNA Metabolite KEGG Compound
Orotate Metabolite KEGG Compound
CDP Metabolite KEGG Compound
3-Ureidopropionate Metabolite KEGG Compound
Uridine Metabolite HMDB
DHODH GeneProduct Entrez Gene
CMPK1 GeneProduct Entrez Gene
5,6-Dihydrouracil Metabolite KEGG Compound
ENTPD4 GeneProduct NCBI Protein
Uracil Metabolite HMDB
PNPT1 GeneProduct Entrez Gene
TYMP GeneProduct Entrez Gene
ENPP1 GeneProduct Entrez Gene
DTYMK GeneProduct Entrez Gene
dTDP Metabolite KEGG Compound
DUT GeneProduct Entrez Gene
Thymidine Metabolite HMDB
dUDP Metabolite KEGG Compound
RRM2 GeneProduct Entrez Gene
Deoxyuridine Metabolite HMDB
UPP2 GeneProduct Enzyme Nomenclature
DCTPP1 GeneProduct Entrez Gene
dUMP Metabolite KEGG Compound
CAD GeneProduct Entrez Gene
UMPS GeneProduct Entrez Gene
dCTP Metabolite KEGG Compound
dCDP Metabolite KEGG Compound
DCTD GeneProduct Entrez Gene
DTYMK GeneProduct Entrez Gene
CAD GeneProduct Entrez Gene
Carbamoylphosphate Metabolite HMDB
UPB1 GeneProduct Entrez Gene
Orotidine 5'-phosphate Metabolite KEGG Compound
RRM1 GeneProduct Entrez Gene
UMP Metabolite HMDB
UTP Metabolite KEGG Compound
Deoxycytidine Metabolite KEGG Compound
L-Glutamine Metabolite HMDB
UPRT GeneProduct Entrez Gene
dTMP Metabolite KEGG Compound
Thymine Metabolite HMDB
UCK1 GeneProduct Entrez Gene
UCK2 GeneProduct Entrez Gene
NT5C GeneProduct Entrez Gene
CDA GeneProduct Entrez Gene
NT5C GeneProduct Entrez Gene
NT5C GeneProduct Entrez Gene
NT5C GeneProduct Entrez Gene
TK1 GeneProduct Entrez Gene
TK2 GeneProduct Entrez Gene
TK1 GeneProduct Entrez Gene
CMPK2 GeneProduct Entrez Gene
CMPK1 GeneProduct Entrez Gene
CMPK2 GeneProduct Entrez Gene
CMPK1 GeneProduct Entrez Gene
CMPK2 GeneProduct Entrez Gene
DCK GeneProduct Entrez Gene
ENPP3 GeneProduct Entrez Gene
RRM2B GeneProduct Entrez Gene
RRM2 GeneProduct Entrez Gene
RRM1 GeneProduct Entrez Gene
RRM2B GeneProduct Entrez Gene
ENPP1 GeneProduct Entrez Gene
ENPP3 GeneProduct Entrez Gene
ENPP1 GeneProduct Entrez Gene
ENPP3 GeneProduct Entrez Gene
ENTPD3 GeneProduct Entrez Gene
ENTPD1 GeneProduct Entrez Gene
ENTPD8 GeneProduct NCBI Protein
ENTPD3 GeneProduct NCBI Protein
ENTPD1 GeneProduct NCBI Protein
ENTPD3 GeneProduct Entrez Gene
ENTPD1 GeneProduct Entrez Gene
NME1-NME2 GeneProduct Entrez Gene
NME1 GeneProduct Entrez Gene
NME2 GeneProduct Entrez Gene
NME3 GeneProduct Entrez Gene
NME4 GeneProduct Entrez Gene
NME6 GeneProduct Entrez Gene
NME7 GeneProduct Entrez Gene
NME1 GeneProduct Entrez Gene
NME GeneProduct Enzyme Nomenclature
NME GeneProduct Enzyme Nomenclature
NME GeneProduct Enzyme Nomenclature
NME GeneProduct Enzyme Nomenclature
PNP GeneProduct NCBI Protein
UPP1 GeneProduct Entrez Gene
UPP2 GeneProduct Enzyme Nomenclature
UPP1 GeneProduct Entrez Gene
CTPS2 GeneProduct Entrez Gene
UCKL1 GeneProduct Entrez Gene
UCK1 GeneProduct Entrez Gene
UCK2 GeneProduct Entrez Gene
UCKL1 GeneProduct Entrez Gene
NT5M GeneProduct Entrez Gene
NT5M GeneProduct Entrez Gene
NT5E GeneProduct NCBI Protein
NT5M GeneProduct Entrez Gene
ZNRD1 GeneProduct Entrez Gene
POLR1A GeneProduct Entrez Gene
PRIM2 GeneProduct Entrez Gene
POLA1 GeneProduct Entrez Gene
POLR2A GeneProduct Entrez Gene
POLR2G GeneProduct Entrez Gene
POLR2K GeneProduct Entrez Gene
POLR3D GeneProduct Entrez Gene
POLR3H GeneProduct Entrez Gene
POLR1B GeneProduct Entrez Gene
POLR1C GeneProduct Entrez Gene
POLR1D GeneProduct Entrez Gene
POLR1E GeneProduct Entrez Gene
POLR2B GeneProduct Entrez Gene
POLR2C GeneProduct Entrez Gene
POLR2D GeneProduct Entrez Gene
POLR2E GeneProduct Entrez Gene
POLR2H GeneProduct Entrez Gene
POLR2J1 GeneProduct Entrez Gene
POLR2J2 GeneProduct Entrez Gene
POLR2J3 GeneProduct Entrez Gene
POLR2L GeneProduct Entrez Gene
POLR3A GeneProduct Entrez Gene
POLR3B GeneProduct Entrez Gene
POLR3C GeneProduct Entrez Gene
POLR3E GeneProduct Entrez Gene
POLR3F GeneProduct Entrez Gene
POLR3G GeneProduct Entrez Gene
POLR3GL GeneProduct Entrez Gene
POLR3K GeneProduct Entrez Gene
POLR2I GeneProduct Entrez Gene
TWISTNB GeneProduct Entrez Gene
POLD1 GeneProduct Entrez Gene
POLD3 GeneProduct Entrez Gene
POLE1 GeneProduct Entrez Gene
POLE3 GeneProduct Entrez Gene
PRIM1 GeneProduct Entrez Gene
POLA2 GeneProduct Entrez Gene
POLD2 GeneProduct Entrez Gene
POLD4 GeneProduct Entrez Gene
POLE2 GeneProduct Entrez Gene
POLE4 GeneProduct Entrez Gene
Diphosphate Metabolite ChEBI
PRPP Metabolite KEGG Compound
UMPS GeneProduct Entrez Gene
Diphosphate Metabolite ChEBI
NT5C GeneProduct Entrez Gene
NT5M GeneProduct Entrez Gene
TYMP GeneProduct Entrez Gene
NT5E GeneProduct NCBI Protein
NT5E GeneProduct NCBI Protein
(R)-dihydrothymine Metabolite KEGG Compound
(R)-3-ureidoisobutyrate Metabolite KEGG Compound
(R)-3-aminoisobutyrate Metabolite KEGG Compound
Valine, leucine and isoleucine metabolism Pathway None
DPYD GeneProduct Entrez Gene
DPYS GeneProduct NCBI Protein
UPB1 GeneProduct Entrez Gene
ENTPD8 GeneProduct NCBI Protein
ENTPD3 GeneProduct Entrez Gene
ENTPD1 GeneProduct Entrez Gene
NT5M GeneProduct Entrez Gene
AK9 GeneProduct NCBI Protein
AK9 GeneProduct NCBI Protein
ENTPD8 GeneProduct NCBI Protein
ENTPD3 GeneProduct Entrez Gene
ENTPD1 GeneProduct Entrez Gene
NT5E GeneProduct NCBI Protein
NT5E GeneProduct NCBI Protein
ENTPD6 GeneProduct NCBI Protein
ENTPD5 GeneProduct NCBI Protein
CANT1 GeneProduct NCBI Protein
AK9 GeneProduct NCBI Protein
ENTPD1 GeneProduct NCBI Protein
ENTPD3 GeneProduct NCBI Protein
ENTPD8 GeneProduct NCBI Protein

References