Pyrimidine metabolism (WP4022)

Homo sapiens

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]

Authors

Anna Hoekstra , Denise Slenter , Kristina Hanspers , Finterly Hu , Eric Weitz , and Egon Willighagen

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

pyrimidine metabolic pathway

Participants

Label Type Compact URI Comment
UppppU Metabolite kegg.compound:C06198 P1,P4-Bis(5'-uridyl) tetraphosphate
UDP Metabolite kegg.compound:C00015
2-deoxy-D-ribose-1P Metabolite pubchem.compound:439287
DNA Metabolite kegg.compound:C00039
dTTP Metabolite kegg.compound:C00459 Deoxythymidine 5'-triphosphate
dCMP Metabolite kegg.compound:C00239
CMP Metabolite hmdb:HMDB0000095
N-Carbamoylaspartate Metabolite hmdb:HMDB0000828
dUTP Metabolite kegg.compound:C00460
Cytidine Metabolite hmdb:HMDB0000089
PRPP Metabolite kegg.compound:C00119 5-Phospho-alpha-D-ribose 1-diphosphate
Dihydroorotate Metabolite hmdb:HMDB0003349
beta-Alanine Metabolite hmdb:HMDB0000056
CTP Metabolite kegg.compound:C00063
RNA Metabolite kegg.compound:C00046
Orotate Metabolite kegg.compound:C00295
CDP Metabolite kegg.compound:C00112
3-Ureidopropionate Metabolite kegg.compound:C02642
Uridine Metabolite hmdb:HMDB0000296
5,6-Dihydrouracil Metabolite kegg.compound:C00429
Uracil Metabolite hmdb:HMDB0000300
dTDP Metabolite kegg.compound:C00363 Deoxythymidine 5'-diphosphate
Thymidine Metabolite hmdb:HMDB0000273
dUDP Metabolite kegg.compound:C01346
Deoxyuridine Metabolite hmdb:HMDB0000012
dUMP Metabolite kegg.compound:C00365
dCTP Metabolite kegg.compound:C00458
dCDP Metabolite kegg.compound:C00705
Carbamoylphosphate Metabolite hmdb:HMDB0001096
Orotidine 5'-phosphate Metabolite kegg.compound:C01103
UMP Metabolite hmdb:HMDB0000288
UTP Metabolite kegg.compound:C00075
Deoxycytidine Metabolite kegg.compound:C00881
L-Glutamine Metabolite hmdb:HMDB0000641
dTMP Metabolite kegg.compound:C00364 Deoxythymidine 5'-phosphate
Thymine Metabolite hmdb:HMDB0000262
Diphosphate Metabolite chebi:45212
(R)-dihydrothymine Metabolite kegg.compound:C21028
(R)-3-ureidoisobutyrate Metabolite kegg.compound:C21029
(R)-3-aminoisobutyrate Metabolite kegg.compound:C01205
AK9 GeneProduct ncbiprotein:NP_001138600
NUDT2 GeneProduct ncbiprotein:NP_001152
PNPT1 GeneProduct ncbiprotein:NP_149100
CDA GeneProduct ncbigene:978 Original kegg element: gene;48;mtu:Rv3315c
DPYS GeneProduct ncbigene:1807
TYMS GeneProduct ncbigene:7298 Original kegg element: gene;6;mtu:Rv2754c
TK2 GeneProduct ncbigene:7084
CAD GeneProduct ncbigene:790 Original kegg element: gene;14;mtu:Rv1380
CTPS1 GeneProduct ncbigene:1503 Original kegg element: gene;25;mtu:Rv0321
DPYD GeneProduct ncbigene:1806
ENTPD8 GeneProduct ncbiprotein:NP_001028285
DHODH GeneProduct ncbigene:1723 Original kegg element: gene;17;mtu:Rv2139
CMPK1 GeneProduct ncbigene:51727 Original kegg element: gene;4;mtu:Rv2883c
ENTPD4 GeneProduct ncbiprotein:NP_004892 Original kegg element: gene;111;mtu:Rv1021
PNPT1 GeneProduct ncbigene:87178 Original kegg element: gene;41;mtu:Rv2783c
TYMP GeneProduct ncbigene:1890
ENPP1 GeneProduct ncbigene:5167 Original kegg element: gene;26;mtu:Rv1699
DTYMK GeneProduct ncbigene:1841 Original kegg element: gene;73;mtu:Rv3247c
DUT GeneProduct ncbigene:1854 Original kegg element: gene;70;mtu:Rv2697c
RRM2 GeneProduct ncbigene:6241 Original kegg element: gene;60;mtu:Rv0233 mtu:Rv0570 mtu:Rv1981c mtu:Rv3048c mtu:Rv3051c
UPP2 GeneProduct eccode:151531 Check literature for directionality of enzyme
DCTPP1 GeneProduct ncbigene:79077
CAD GeneProduct ncbigene:790 Original kegg element: gene;8;mtu:Rv1383 mtu:Rv1384
UMPS GeneProduct ncbigene:7372 Original kegg element: gene;106;mtu:Rv1385
DCTD GeneProduct ncbigene:1635
DTYMK GeneProduct ncbigene:1841 Original kegg element: gene;85;mtu:Rv3247c
CAD GeneProduct ncbigene:790 Original kegg element: gene;15;mtu:Rv1381
UPB1 GeneProduct ncbigene:51733
RRM1 GeneProduct ncbigene:6240 Original kegg element: gene;60;mtu:Rv0233 mtu:Rv0570 mtu:Rv1981c mtu:Rv3048c mtu:Rv3051c
UPRT GeneProduct ncbigene:139596
UCK1 GeneProduct ncbigene:83549
UCK2 GeneProduct ncbigene:7371
NT5C GeneProduct ncbigene:30833
TK1 GeneProduct ncbigene:7083
CMPK2 GeneProduct ncbigene:129607 Original kegg element: gene;4;mtu:Rv2883c
DCK GeneProduct ncbigene:1633
ENPP3 GeneProduct ncbigene:5169 Original kegg element: gene;26;mtu:Rv1699
RRM2B GeneProduct ncbigene:50484 Original kegg element: gene;60;mtu:Rv0233 mtu:Rv0570 mtu:Rv1981c mtu:Rv3048c mtu:Rv3051c
ENTPD3 GeneProduct ncbigene:956
ENTPD1 GeneProduct ncbigene:953
ENTPD3 GeneProduct ncbiprotein:NP_001239
ENTPD1 GeneProduct ncbiprotein:NP_001767
NME1-NME2 GeneProduct ncbigene:654364
NME1 GeneProduct ncbigene:4830
NME2 GeneProduct ncbigene:4831
NME3 GeneProduct ncbigene:4832
NME4 GeneProduct ncbigene:4833
NME6 GeneProduct ncbigene:10201
NME7 GeneProduct ncbigene:29922
NME GeneProduct eccode:2.7.4.6
NME GeneProduct eccode:2.7.4.6 Check literature for directionality of enzyme
PNP GeneProduct ncbiprotein:NP_000261
UPP1 GeneProduct ncbigene:7378 Check literature for directionality of enzyme
CTPS2 GeneProduct ncbigene:56474 Original kegg element: gene;25;mtu:Rv0321
UCKL1 GeneProduct ncbigene:54963
NT5M GeneProduct ncbigene:56953
NT5E GeneProduct ncbiprotein:NP_002517
ZNRD1 GeneProduct ncbigene:30834
POLR1A GeneProduct ncbigene:25885
PRIM2 GeneProduct ncbigene:5558
POLA1 GeneProduct ncbigene:5422
POLR2A GeneProduct ncbigene:5430
POLR2G GeneProduct ncbigene:5436
POLR2K GeneProduct ncbigene:5440
POLR3D GeneProduct ncbigene:661
POLR3H GeneProduct ncbigene:171568
POLR1B GeneProduct ncbigene:84172
POLR1C GeneProduct ncbigene:9533
POLR1D GeneProduct ncbigene:51082
POLR1E GeneProduct ncbigene:64425
POLR2B GeneProduct ncbigene:5431
POLR2C GeneProduct ncbigene:5432
POLR2D GeneProduct ncbigene:5433
POLR2E GeneProduct ncbigene:5434
POLR2H GeneProduct ncbigene:5437
POLR2J1 GeneProduct ncbigene:5439
POLR2J2 GeneProduct ncbigene:246721
POLR2J3 GeneProduct ncbigene:548644
POLR2L GeneProduct ncbigene:5441
POLR3A GeneProduct ncbigene:11128
POLR3B GeneProduct ncbigene:55703
POLR3C GeneProduct ncbigene:10623
POLR3E GeneProduct ncbigene:55718
POLR3F GeneProduct ncbigene:10621
POLR3G GeneProduct ncbigene:10622
POLR3GL GeneProduct ncbigene:84265
POLR3K GeneProduct ncbigene:51728
POLR2I GeneProduct ncbigene:5438
TWISTNB GeneProduct ncbigene:221830
POLD1 GeneProduct ncbigene:5424
POLD3 GeneProduct ncbigene:10714
POLE1 GeneProduct ncbigene:5426
POLE3 GeneProduct ncbigene:54107
PRIM1 GeneProduct ncbigene:5557
POLA2 GeneProduct ncbigene:23649
POLD2 GeneProduct ncbigene:5425
POLD4 GeneProduct ncbigene:57804
POLE2 GeneProduct ncbigene:5427
POLE4 GeneProduct ncbigene:56655
UMPS GeneProduct ncbigene:7372 Check literature for directionality of enzyme
DPYS GeneProduct ncbiprotein:NP_001376
AK9 GeneProduct ncbiprotein:NP_001138600 Check literature for directionality of enzyme
ENTPD6 GeneProduct ncbiprotein:NP_001238 Original kegg element: gene;111;mtu:Rv1021
ENTPD5 GeneProduct ncbiprotein:NP_001240 Original kegg element: gene;111;mtu:Rv1021
CANT1 GeneProduct ncbiprotein:NP_001153244 Original kegg element: gene;111;mtu:Rv1021

References

  1. KEGG Pathway: map00240