DE NOVO PYRIMIDINE BIOSYNTHETIC PATHWAY (PW:0000862) Description
Mammalian de novo pyrimidine biosynthesis is accomplished by six enzymatic activities, encoded by only three genes - two encode multifunctional proteins. In the de novo synthesis of pyrimidines, the pyrimidine ring is added to the ribose-5-phosphate after the ring has been generated, unlike purines. The first reaction of the six-step pathway to generate uridine monophosphate (UMP) is catalyzed by the carbamoyl phosphate synthetase II activity of the trifunctional cytosolic mammalian enzyme Cad, generating carbamoyl phosphate from carbonate and the amide nitrogen of glutamine. Carbamoyl phosphate, which is highlighted along with the other central pathway products, can also be supplied from arginine and proline metabolism. Carbonate contributes one carbon and glutamine supplies one of the two nitrogens to the pyrimidine ring. This reaction requires two molecules of ATP and is the rate-limiting step in pyrimidine biosynthesis, being feedback inhibited by uridine diphosphate and uridine triphosphate, and activated by phosphoribosyl pyrophosphate (PRPP) and ATP. Carbamoyl aspartate is then generated via the condensation of carbamoyl phosphate with aspartate, catalyzed by the second enzymatic activity of Cad, aspartate transcarbamoylase. Aspartate contributes three carbons and a nitrogen to the pyrimidine ring. Closure of the ring to generate dihydroorotate is performed by the last activity of Cad, dihydroorotase. Dihydroorotate is oxidized to orotate by dihydroorotate dehydrogenase (Dhodh), the only pathway enzyme located in the mitochondrion. Quinones supply the oxidizing power. This link to the respiratory chain makes pyrimidine biosynthesis a pacemaker for cell growth and division under limited oxygen conditions. Orotate is combined with PRPP, from the pentose phosphate pathway, to generate orotidine-5'-monophosphate (OMP), catalyzed by the first enzyme activity of the bifunctional enzyme Umps, orotate phosphoribosyl transferase. OMP is then decarboxylated to form uridine monophosphate (UMP) by OMP decarboxylase, the other activity of Umps. A second level of control is exerted here, with UMP and cytididine monophosphate (CMP; not shown) negatively regulating Umps, and PRPP positively regulating both activities. Increased expression of Cad and Dhodh are associated with certain cancers, while diabetes is associated with decreased expression of Cad, Dhodh and Umps. UMP is the precursor for all pyrimidine nucleotides. The di- and triphosphorylated forms are generated by cytidine monophosphate (UMP-CMP) kinase (Cmpk1 and 2), and isoforms of nucleoside diphosphate kinases (Nme1-6). Uridine triphosphate (UTP) is aminated to form cytosine triphosphate (CTP) by CTP synthase isoforms (Ctps, Ctps2). The diphosphorylated nucleotides are used to form deoxypyrimidine nucleotides. CTP and UTP are directly incorporated into RNA, and CTP is important in one of the pathways of phospholipid biosynthesis. Uracil nucleotides are essential in the formation of nucleotide sugars such as UDP-glucose, used for glycosylation reactions, and UDP-N-acetylglucosamine, used in protein glycosylation. UDP and UTP also serve as signaling molecules operating through metabotropic receptors.
To see the Ontology Report for annotations, GViewer and download click here [Click here to see the ontology report for associated GO term -
GO:0044205 , KEGG map -
map00240 and entry at Reactome -
REACT_73848 ]
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Pathway Diagram:
GO TO:
Genes in Pathway:
Symbol Object Name
Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G
Cad
carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase
ISO
RGD
PMID:15096496 RGD:5133412
NCBI chr 6:25,292,133...25,315,078
G
Cmpk1
cytidine/uridine monophosphate kinase 1
ISO
RGD
PMID:12678497 RGD:5133414
NCBI chr 5:128,480,301...128,507,830
G
Cmpk2
cytidine/uridine monophosphate kinase 2
IDA
RGD
PMID:192455 RGD:5133256
NCBI chr 6:48,802,150...48,813,652
G
Ctps1
CTP synthase 1
ISO
RGD
PMID:12678497 RGD:5133414
NCBI chr 5:134,125,022...134,154,155
G
Ctps2
CTP synthase 2
ISO
RGD
PMID:20739275 RGD:5133419
NCBI chr X:31,645,873...31,786,733
G
Dhodh
dihydroorotate dehydrogenase
ISO
RGD
PMID:15096496 RGD:5133412
NCBI chr19:37,551,858...37,573,327
G
Nme1
NME/NM23 nucleoside diphosphate kinase 1
ISO
RGD
PMID:11768308 RGD:5134680
NCBI chr10:79,403,939...79,426,620
G
Nme2
NME/NM23 nucleoside diphosphate kinase 2
ISO
RGD
PMID:11768308 RGD:5134680
NCBI chr10:79,394,999...79,400,418
G
Nme3
NME/NM23 nucleoside diphosphate kinase 3
ISO
RGD
PMID:11768308 RGD:5134680
NCBI chr10:13,917,309...13,918,415
G
Nme4
NME/NM23 nucleoside diphosphate kinase 4
ISO
RGD
PMID:11768308 RGD:5134680
NCBI chr10:15,114,624...15,118,479
G
Nme6
NME/NM23 nucleoside diphosphate kinase 6
ISO
RGD
PMID:11768308 RGD:5134680
NCBI chr 8:109,832,085...109,839,301
G
Umps
uridine monophosphate synthetase
ISO
RGD
PMID:15096496 RGD:5133412
NCBI chr11:66,806,107...66,816,520
Additional Elements in Pathway: (includes Gene Groups, Small Molecules, Other Pathways..etc.) Small Molecule ADP adenosine diphosphate Small Molecule ATP adenosine triphosphate Small Molecule CDP cytidine diphosphate Small Molecule CTP cytidine triphosphate Functional Class Nme members members of the nucleoside diphosphate kinase family Small Molecule PRPP phosphoribosyl pyrophosphate Small Molecule UDP uridine diphosphate Small Molecule UMP uridine monophosphate Small Molecule UTP uridine triphosphate
Pathway Gene Annotations
Disease Annotations Associated with Genes in the de novo pyrimidine biosynthetic pathway
Cad beta thalassemia , Colonic Neoplasms , congenital hypoplastic anemia , Coronary Artery Disease, Autosomal Dominant 2 , developmental and epileptic encephalopathy 1 , developmental and epileptic encephalopathy 50 , epilepsy , erythroleukemia , Experimental Diabetes Mellitus , Experimental Liver Neoplasms , Experimental Mammary Neoplasms , Fetal Growth Retardation , genetic disease , hepatocellular carcinoma , hereditary spherocytosis , Meniere's disease , renal cell carcinoma , rhabdomyosarcoma , sickle cell anemia , Tatton-Brown-Rahman syndrome Cmpk1 congenital aphakia , lung non-small cell carcinoma Cmpk2 Idiopathic Basal Ganglia Calcification 10 , multiple sclerosis Ctps1 biliary tract benign neoplasm , Charcot-Marie-Tooth disease dominant intermediate C , immunodeficiency 24 , Nasopharyngeal Neoplasms Ctps2 autistic disorder , colorectal cancer , Laterality Defects, Autosomal Dominant , Neurodevelopmental Disorders , syndromic X-linked intellectual disability Lubs type Dhodh autosomal dominant dyskeratosis congenita 6 , beta thalassemia , erythroleukemia , Experimental Arthritis , Experimental Autoimmune Neuritis , Experimental Diabetes Mellitus , Experimental Liver Neoplasms , genetic disease , hereditary spherocytosis , Immediate Hypersensitivity , postaxial acrofacial dysostosis , sickle cell anemia , Transplant Rejection Nme1 breast cancer , breast carcinoma , Cardiomegaly , Colorectal Neoplasms , COVID-19 , hepatocellular carcinoma , hereditary breast ovarian cancer syndrome , hypertrophic cardiomyopathy , Hypoxia , Lymphatic Metastasis , Neoplasm Invasiveness , Neoplasm Metastasis , neuroblastoma , ovarian cancer , ovary epithelial cancer , pancreatic ductal carcinoma , prostate carcinoma , renal cell carcinoma , squamous cell carcinoma , teratoma , urinary bladder cancer Nme2 arteriosclerosis , Chemical and Drug Induced Liver Injury , Colorectal Neoplasms , congestive heart failure , Germ Cell and Embryonal Neoplasms , hereditary breast ovarian cancer syndrome , Lymphatic Metastasis , Mesothelioma , Neoplasm Metastasis , osteoarthritis , ovarian cancer , ovarian carcinoma , Ovarian Neoplasms , prostatic hypertrophy , Skin Neoplasms , teratoma , urinary bladder cancer Nme3 epilepsy , Idiopathic Generalized Epilepsy , short-rib thoracic dysplasia 9 with or without polydactyly , tuberous sclerosis 2 Nme4 epilepsy , Idiopathic Generalized Epilepsy , short-rib thoracic dysplasia 9 with or without polydactyly Nme6 Progressive Microcephaly with Seizures and Cerebral and Cerebellar Atrophy Umps alkaptonuria , beta thalassemia , Breast Neoplasms , cardiomyopathy , Colonic Neoplasms , Colorectal Neoplasms , congenital hypoplastic anemia , Drug-Related Side Effects and Adverse Reactions , erythroleukemia , Experimental Diabetes Mellitus , familial hypocalciuric hypercalcemia , Familial Thoracic Aortic Aneurysm 7 , genetic disease , hepatocellular carcinoma , hereditary spherocytosis , Mouth Neoplasms , orotic aciduria , Orotic Aciduria II , Primary Lymphedema with Myelodysplasia , Prostatic Neoplasms , purine-pyrimidine metabolic disorder , sickle cell anemia , squamous cell carcinoma , Stomach Neoplasms
alkaptonuria Umps arteriosclerosis Nme2 autistic disorder Ctps2 autosomal dominant dyskeratosis congenita 6 Dhodh beta thalassemia Cad , Dhodh , Umps biliary tract benign neoplasm Ctps1 breast cancer Nme1 breast carcinoma Nme1 Breast Neoplasms Umps Cardiomegaly Nme1 cardiomyopathy Umps Charcot-Marie-Tooth disease dominant intermediate C Ctps1 Chemical and Drug Induced Liver Injury Nme2 Colonic Neoplasms Cad , Umps colorectal cancer Ctps2 Colorectal Neoplasms Nme1 , Nme2 , Umps congenital aphakia Cmpk1 congenital hypoplastic anemia Cad , Umps congestive heart failure Nme2 Coronary Artery Disease, Autosomal Dominant 2 Cad COVID-19 Nme1 developmental and epileptic encephalopathy 1 Cad developmental and epileptic encephalopathy 50 Cad Drug-Related Side Effects and Adverse Reactions Umps epilepsy Cad , Nme3 , Nme4 erythroleukemia Cad , Dhodh , Umps Experimental Arthritis Dhodh Experimental Autoimmune Neuritis Dhodh Experimental Diabetes Mellitus Cad , Dhodh , Umps Experimental Liver Neoplasms Cad , Dhodh Experimental Mammary Neoplasms Cad familial hypocalciuric hypercalcemia Umps Familial Thoracic Aortic Aneurysm 7 Umps Fetal Growth Retardation Cad genetic disease Cad , Dhodh , Umps Germ Cell and Embryonal Neoplasms Nme2 hepatocellular carcinoma Cad , Nme1 , Umps hereditary breast ovarian cancer syndrome Nme1 , Nme2 hereditary spherocytosis Cad , Dhodh , Umps hypertrophic cardiomyopathy Nme1 Hypoxia Nme1 Idiopathic Basal Ganglia Calcification 10 Cmpk2 Idiopathic Generalized Epilepsy Nme3 , Nme4 Immediate Hypersensitivity Dhodh immunodeficiency 24 Ctps1 Laterality Defects, Autosomal Dominant Ctps2 lung non-small cell carcinoma Cmpk1 Lymphatic Metastasis Nme1 , Nme2 Meniere's disease Cad Mesothelioma Nme2 Mouth Neoplasms Umps multiple sclerosis Cmpk2 Nasopharyngeal Neoplasms Ctps1 Neoplasm Invasiveness Nme1 Neoplasm Metastasis Nme1 , Nme2 neuroblastoma Nme1 Neurodevelopmental Disorders Ctps2 orotic aciduria Umps Orotic Aciduria II Umps osteoarthritis Nme2 ovarian cancer Nme1 , Nme2 ovarian carcinoma Nme2 Ovarian Neoplasms Nme2 ovary epithelial cancer Nme1 pancreatic ductal carcinoma Nme1 postaxial acrofacial dysostosis Dhodh Primary Lymphedema with Myelodysplasia Umps Progressive Microcephaly with Seizures and Cerebral and Cerebellar Atrophy Nme6 prostate carcinoma Nme1 prostatic hypertrophy Nme2 Prostatic Neoplasms Umps purine-pyrimidine metabolic disorder Umps renal cell carcinoma Cad , Nme1 rhabdomyosarcoma Cad short-rib thoracic dysplasia 9 with or without polydactyly Nme3 , Nme4 sickle cell anemia Cad , Dhodh , Umps Skin Neoplasms Nme2 squamous cell carcinoma Nme1 , Umps Stomach Neoplasms Umps syndromic X-linked intellectual disability Lubs type Ctps2 Tatton-Brown-Rahman syndrome Cad teratoma Nme1 , Nme2 Transplant Rejection Dhodh tuberous sclerosis 2 Nme3 urinary bladder cancer Nme1 , Nme2
Pathway Annotations Associated with Genes in the de novo pyrimidine biosynthetic pathway
Cad 2-hydroxyglutaric aciduria pathway , alanine, aspartate and glutamate metabolic pathway , beta-ureidopropionase deficiency pathway , Canavan disease pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , glutamic acid/glutamate metabolic pathway , homocarnosinosis pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , orotic aciduria 1 pathway , pyrimidine metabolic pathway , succinic semialdehyde dehydrogenase deficiency pathway Cmpk1 de novo pyrimidine biosynthetic pathway , gemcitabine pharmacodynamics pathway , gemcitabine pharmacokinetics pathway , Glut1 deficiency syndrome pathway , lactose biosynthetic pathway , lamivudine pharmacokinetics pathway , pyrimidine metabolic pathway Cmpk2 beta-ureidopropionase deficiency pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , orotic aciduria 1 pathway , pyrimidine metabolic pathway Ctps1 beta-ureidopropionase deficiency pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , gemcitabine pharmacodynamics pathway , gemcitabine pharmacokinetics pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , orotic aciduria 1 pathway , pyrimidine metabolic pathway Ctps2 de novo pyrimidine biosynthetic pathway , pyrimidine metabolic pathway Dhodh beta-ureidopropionase deficiency pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , orotic aciduria 1 pathway , pyrimidine metabolic pathway Nme1 adefovir pharmacokinetics pathway , de novo pyrimidine biosynthetic pathway , E-cadherin signaling pathway , gemcitabine pharmacodynamics pathway , gemcitabine pharmacokinetics pathway , lamivudine pharmacokinetics pathway , purine metabolic pathway , pyrimidine metabolic pathway , tenofovir pharmacokinetics pathway Nme2 adefovir pharmacokinetics pathway , de novo pyrimidine biosynthetic pathway , Glut1 deficiency syndrome pathway , lactose biosynthetic pathway , purine metabolic pathway , pyrimidine metabolic pathway , tenofovir pharmacokinetics pathway Nme3 de novo pyrimidine biosynthetic pathway , purine metabolic pathway , pyrimidine metabolic pathway Nme4 cardiolipin metabolic pathway , de novo pyrimidine biosynthetic pathway , purine metabolic pathway , pyrimidine metabolic pathway Nme6 adenine phoshoribosyltransferase deficiency pathway , adenosine monophosphate deaminase deficiency pathway , adenylosuccinate lyase deficiency pathway , AICA-ribosuria pathway , azathioprine pharmacodynamics pathway , beta-ureidopropionase deficiency pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , Kelley-Seegmiller syndrome pathway , Lesch-Nyhan syndrome pathway , mercaptopurine pharmacodynamics pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , molybdenum cofactor deficiency pathway , orotic aciduria 1 pathway , purine metabolic pathway , purine nucleoside phosphorylase deficiency pathway , pyrimidine metabolic pathway , tioguanine pharmacodynamics pathway , xanthinuria type I pathway , xanthinuria pathway , xanthinuria type II pathway Umps beta-ureidopropionase deficiency pathway , de novo pyrimidine biosynthetic pathway , dihydropyrimidinase deficiency pathway , mitochondrial neurogastrointestinal encephalopathy syndrome pathway , orotic aciduria 1 pathway , pyrimidine metabolic pathway
2-hydroxyglutaric aciduria pathway Cad adefovir pharmacokinetics pathway Nme1 , Nme2 adenine phoshoribosyltransferase deficiency pathway Nme6 adenosine monophosphate deaminase deficiency pathway Nme6 adenylosuccinate lyase deficiency pathway Nme6 AICA-ribosuria pathway Nme6 alanine, aspartate and glutamate metabolic pathway Cad azathioprine pharmacodynamics pathway Nme6 beta-ureidopropionase deficiency pathway Cad , Cmpk2 , Ctps1 , Dhodh , Nme6 , Umps Canavan disease pathway Cad cardiolipin metabolic pathway Nme4 de novo pyrimidine biosynthetic pathway Cad , Cmpk1 , Cmpk2 , Ctps1 , Ctps2 , Dhodh , Nme1 , Nme2 , Nme3 , Nme4 , Nme6 , Umps dihydropyrimidinase deficiency pathway Cad , Cmpk2 , Ctps1 , Dhodh , Nme6 , Umps E-cadherin signaling pathway Nme1 gemcitabine pharmacodynamics pathway Cmpk1 , Ctps1 , Nme1 gemcitabine pharmacokinetics pathway Cmpk1 , Ctps1 , Nme1 Glut1 deficiency syndrome pathway Cmpk1 , Nme2 glutamic acid/glutamate metabolic pathway Cad homocarnosinosis pathway Cad Kelley-Seegmiller syndrome pathway Nme6 lactose biosynthetic pathway Cmpk1 , Nme2 lamivudine pharmacokinetics pathway Cmpk1 , Nme1 Lesch-Nyhan syndrome pathway Nme6 mercaptopurine pharmacodynamics pathway Nme6 mitochondrial neurogastrointestinal encephalopathy syndrome pathway Cad , Cmpk2 , Ctps1 , Dhodh , Nme6 , Umps molybdenum cofactor deficiency pathway Nme6 orotic aciduria 1 pathway Cad , Cmpk2 , Ctps1 , Dhodh , Nme6 , Umps purine metabolic pathway Nme1 , Nme2 , Nme3 , Nme4 , Nme6 purine nucleoside phosphorylase deficiency pathway Nme6 pyrimidine metabolic pathway Cad , Cmpk1 , Cmpk2 , Ctps1 , Ctps2 , Dhodh , Nme1 , Nme2 , Nme3 , Nme4 , Nme6 , Umps succinic semialdehyde dehydrogenase deficiency pathway Cad tenofovir pharmacokinetics pathway Nme1 , Nme2 tioguanine pharmacodynamics pathway Nme6 xanthinuria type I pathway Nme6 xanthinuria pathway Nme6 xanthinuria type II pathway Nme6
References Associated with the de novo pyrimidine biosynthetic pathway:
Arima T, etal., Cancer Res. 1977 Jun;37(6):1593-7.
Evans DR and Guy HI, J Biol Chem. 2004 Aug 6;279(32):33035-8. Epub 2004 Apr 19.
Huang M and Graves LM, Cell Mol Life Sci. 2003 Feb;60(2):321-36.
Kassel KM, etal., J Biol Chem. 2010 Oct 29;285(44):33727-36. Epub 2010 Aug 25.
Lacombe ML, etal., J Bioenerg Biomembr. 2000 Jun;32(3):247-58.
Loffler M, etal., Trends Mol Med. 2005 Sep;11(9):430-7.
Nyhan WL Mol Genet Metab. 2005 Sep-Oct;86(1-2):25-33.
Cory JG and Cory AH, In Vivo. 2006 Sep-Oct;20(5):587-9.
Ontology Path Diagram:
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