This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: uridine-5'-phosphate biosynthesis, de novo biosynthesis of uridine-5'-phosphate, de novo biosynthesis of uridine-5'-monophosphate
|Superclasses:||Biosynthesis → Nucleosides and Nucleotides Biosynthesis → Pyrimidine Nucleotide Biosynthesis → Pyrimidine Nucleotides De Novo Biosynthesis → Pyrimidine Ribonucleotides De Novo Biosynthesis|
Pyrimidine and purine nucleoside triphosphates are the activated precursors of DNA and RNA. The pyrimidine deoxyribonucleoside triphosphates dCTP and dTTP are incorporated into DNA while the ribonucleoside triphosphates CTP and UTP are incorporated into RNA. In addition, their diphosphates form activated derivatives of other molecules, such as UDP-α-D-glucose, CMP-3-deoxy-α-D-manno-octulosonate and dTDP-α-D-fucopyranose, for use in biosynthesis of polysaccharides, glycoproteins and phospholipids [Zhou et al., 1998, Giermann02, Schroder et al., 2005, Zrenner06].
In addition to de novo biosynthesis, salvage pathways reutilize exogenous free bases and nucleosides and some of the resulting pyrimidine nucleotides can enter the de novo biosynthesis pathways (see pyrimidine ribonucleosides salvage I, pyrimidine nucleobases salvage I and pyrimidine deoxyribonucleosides salvage). The de novo biosynthetic pathways consume relatively large amounts of high energy phosphate and reducing power, and thus organisms prefer to use salvage pathways when possible. However, the de novo biosynthetic pathways are necessary when exogenous precursors are limiting. In order to conserve resources, the de novo pathways are regulated both by allosteric enzymes and at the gene expression level. These essential, evolutionarily conserved biosynthetic and salvage pathways are found in both prokaryotes and eukaryotes.
The pyrimidine nucleotide de novo biosynthetic pathway derives in part from the central metabolic precursors oxaloacetate and D-ribose 5-phosphate. L-aspartate, a precursor of pyrimidine ribonucleotides, is derived from oxaloacetate, which is generated in the TCA cycle.
About This Pathway
The de novo pyrimidine nucleotide biosynthetic pathway converts hydrogen carbonate, L-glutamine, L-aspartate and 5-phospho-α-D-ribose 1-diphosphate (PRPP) to UMP (uridine 5'-monophosphate), a pyrimidine nucleotide that can be subsequently converted to all other pyrimidine nucleotides (see UTP and CTP de novo biosynthesis).
The first enzyme, carbamoyl phosphate synthetase, forms carbamoyl-phosphate which is not only an intermediate of pyrimidine synthesis but also a precursor for the synthesis of amino acids such as L-arginine, L-citrulline and L-canavanine.
The next step, catalyzed by aspartate transcarbamylase, is the condensation of carbamoyl-phosphate with L-aspartate forming N-carbamoyl-L-aspartate [Nasr et al., 1994], which is cyclized to (S)-dihydroorotate, the first intermediate that contains a pyrimidine ring. (S)-dihydroorotate is oxidized to orotate by dihydroorotate dehydrogenase.
The final two steps, the condensation of orotate with PRPP forming orotidine 5'-phosphate (OMP) followed by the decarboylation of OMP to UMP, are carried out by the enzymes orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase. The last step is considered the rate-limiting step of the overall de novo biosynthesis of pyrimidine nucleotides [Trentmann & Kende, 1995].
In plants, the two initial enzymatic reactions of this pathway occur in the plastids, while all of the remaining reactions occur in the cytosol and mitochondria [Witz et al., 2012]. This implies that N-carbamoyl-L-aspartate must be exported from the plastids. A plastidic nucleobase transporter specific for uracil (a precursor for pyrimidine salvage pathways) has been reported [Witz et al., 2012]. Since the reaction catalyzed by dihydroorotate dehydrogenase occurs in the mitochondria, transporters for both (S)-dihydroorotate and orotate must exist, although they have not been identified yet.
The de novo biosynthesis of pyrimidine nucleotides appears to be one of the most ancient biochemical pathways as it is evolutionary conserved in all species. Although the enzymatic steps in this pathway are conserved throughout all organisms, some differences in the enzymes do exist. For example, in plants and bacteria the three steps leading from carbamoyl-phosphate to orotate are catalyzed by three different proteins, while in mammals they are catalyzed by the single multifunctional CAD protein [Iwahana96]. The last two steps of the pathway are carried out by a bi-functional enzyme (UMP synthase) in plants and animals [Doremus, 1986, Trentmann & Kende, 1995, Gao et al., 1999] whereas bacteria express two separate proteins for that purpose.
Superpathways: superpathway of pyrimidine ribonucleotides de novo biosynthesis , superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis , superpathway of histidine, purine, and pyrimidine biosynthesis
Unification Links: EcoCyc:PWY-5686
Created 24-Oct-2007 by Caspi R , SRI International
Reviewed 24-Oct-2007 by Foerster H , TAIR
Revised 24-Dec-2008 by Caspi R , SRI International
Revised 04-Jan-2013 by Caspi R , SRI International
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Gao et al., 1999: Gao G, Nara T, Nakajima-Shimada J, Aoki T (1999). "Novel organization and sequences of five genes encoding all six enzymes for de novo pyrimidine biosynthesis in Trypanosoma cruzi." J Mol Biol 285(1);149-61. PMID: 9878395
Iwahana96: Iwahana H, Fujimura M, Ii S, Kondo M, Moritani M, Takahashi Y, Yamaoka T, Yoshimoto K, Itakura M (1996). "Molecular cloning of a human cDNA encoding a trifunctional enzyme of carbamoyl-phosphate synthetase-aspartate transcarbamoylase-dihydroorotase in de Novo pyrimidine synthesis." Biochem Biophys Res Commun 219(1);249-55. PMID: 8619816
Nasr et al., 1994: Nasr F, Bertauche N, Dufour ME, Minet M, Lacroute F (1994). "Heterospecific cloning of Arabidopsis thaliana cDNAs by direct complementation of pyrimidine auxotrophic mutants of Saccharomyces cerevisiae. I. Cloning and sequence analysis of two cDNAs catalysing the second, fifth and sixth steps of the de novo pyrimidine biosynthesis pathway." Mol Gen Genet 244(1);23-32. PMID: 8041358
Witz et al., 2012: Witz S, Jung B, Furst S, Mohlmann T (2012). "De novo pyrimidine nucleotide synthesis mainly occurs outside of plastids, but a previously undiscovered nucleobase importer provides substrates for the essential salvage pathway in Arabidopsis." Plant Cell 24(4);1549-59. PMID: 22474184
Zhou et al., 1998: Zhou L, Lacroute F, Thornburg R (1998). "Cloning, expression in Escherichia coli, and characterization of Arabidopsis thaliana UMP/CMP kinase." Plant Physiol 117(1);245-54. PMID: 9576794
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Chen et al., 1998: Chen P, Van Vliet F, Van De Casteele M, Legrain C, Cunin R, Glansdorff N (1998). "Aspartate transcarbamylase from the hyperthermophilic eubacterium Thermotoga maritima: fused catalytic and regulatory polypeptides form an allosteric enzyme." J Bacteriol 1998;180(23);6389-91. PMID: 9829951
Chen89a: Chen KC, Vannais DB, Jones C, Patterson D, Davidson JN (1989). "Mapping of the gene encoding the multifunctional protein carrying out the first three steps of pyrimidine biosynthesis to human chromosome 2." Hum Genet 82(1);40-4. PMID: 2565865
Coleman et al., 1977: Coleman PF, Suttle DP, Stark GR (1977). "Purification from hamster cells of the multifunctional protein that initiates de novo synthesis of pyrimidine nucleotides." J Biol Chem 252(18);6379-85. PMID: 19472
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