MetaCyc Pathway: UMP biosynthesis
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: UMP biosynthesis

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: BiosynthesisNucleosides and Nucleotides BiosynthesisPyrimidine Nucleotide BiosynthesisPyrimidine Nucleotides De Novo BiosynthesisPyrimidine Ribonucleotides De Novo Biosynthesis

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli K-12 substr. MG1655, Homo sapiens

Expected Taxonomic Range: Archaea, Bacteria , Eukaryota

General Background

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-β-D-manno-octulosonate and dTDP-α-D-fucopyranose, for use in biosynthesis of polysaccharides, glycoproteins and phospholipids [Zhou98, Giermann02, Schroder05, 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 [Nasr94], 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 [Trentmann95].

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 [Witz12]. 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 [Witz12]. 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 [Doremus86, Trentmann95, Gao99] 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


Doremus86: Doremus HD (1986). "Organization of the pathway of de novo pyrimidine nucleotide biosynthesis in pea (Pisum sativum L. cv Progress No. 9) leaves." Arch Biochem Biophys 250(1);112-9. PMID: 2876681

Gao99: 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

Giermann02: Giermann N, Schroder M, Ritter T, Zrenner R (2002). "Molecular analysis of de novo pyrimidine synthesis in solanaceous species." Plant Mol Biol 50(3);393-403. PMID: 12369616

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

Nasr94: 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

Schroder05: Schroder M, Giermann N, Zrenner R (2005). "Functional analysis of the pyrimidine de novo synthesis pathway in solanaceous species." Plant Physiol 138(4);1926-38. PMID: 16024685

Trentmann95: Trentmann SM, Kende H (1995). "Analysis of Arabidopsis cDNA that shows homology to the tomato E8 cDNA." Plant Mol Biol 29(1);161-6. PMID: 7579161

Witz12: 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

Zhou98: 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

Zrenner06: Zrenner R, Stitt M, Sonnewald U, Boldt R (2006). "Pyrimidine and purine biosynthesis and degradation in plants." Annu Rev Plant Biol 57;805-36. PMID: 16669783

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Aghajari94: Aghajari N, Jensen KF, Gajhede M (1994). "Crystallization and preliminary X-ray diffraction studies on the Apo form of orotate phosphoribosyltransferase from Escherichia coli." J Mol Biol 241(2);292-4. PMID: 8057372

Alam04: Alam N, Stieglitz KA, Caban MD, Gourinath S, Tsuruta H, Kantrowitz ER (2004). "240s loop interactions stabilize the T state of Escherichia coli aspartate transcarbamoylase." J Biol Chem 279(22);23302-10. PMID: 15014067

Andersen91: Andersen JT, Jensen KF, Poulsen P (1991). "Role of transcription pausing in the control of the pyrE attenuator in Escherichia coli." Mol Microbiol 5(2);327-33. PMID: 1710313

Anderson75a: Anderson PM, Carlson JD (1975). "Reversible reaction of cyanate with a reactive sulfhydryl group at the glutamine binding site of carbamyl phosphate synthetase." Biochemistry 1975;14(16);3688-94. PMID: 240389

Anderson77: Anderson PM (1977). "Binding of allosteric effectors to carbamyl-phosphate synthetase from Escherichia coli." Biochemistry 1977;16(4);587-93. PMID: 189806

Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699

Backstrom86: Backstrom D, Sjoberg RM, Lundberg LG (1986). "Nucleotide sequence of the structural gene for dihydroorotase of Escherichia coli K12." Eur J Biochem 160(1);77-82. PMID: 2876892

Begley00: Begley TP, Appleby TC, Ealick SE (2000). "The structural basis for the remarkable catalytic proficiency of orotidine 5'-monophosphate decarboxylase." Curr Opin Struct Biol 10(6);711-8. PMID: 11114509

Bonekamp84: Bonekamp F, Clemmesen K, Karlstrom O, Jensen KF (1984). "Mechanism of UTP-modulated attenuation at the pyrE gene of Escherichia coli: an example of operon polarity control through the coupling of translation to transcription." EMBO J 3(12);2857-61. PMID: 6098450

Bonekamp85: Bonekamp F, Andersen HD, Christensen T, Jensen KF (1985). "Codon-defined ribosomal pausing in Escherichia coli detected by using the pyrE attenuator to probe the coupling between transcription and translation." Nucleic Acids Res 13(11);4113-23. PMID: 2989788

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Brown91: Brown DC, Collins KD (1991). "Dihydroorotase from Escherichia coli. Substitution of Co(II) for the active site Zn(II)." J Biol Chem 1991;266(3);1597-604. PMID: 1671037

BSUB93: "Bacillus subtilis and Other Gram-Positive Bacteria: Biochemistry, Physiology, and Molecular Genetics." (1993). Editors: Sonenshein, A.L., Hoch, J.A., Losick, R. American Society For Microbiology, Washington, DC.

Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043

Callahan07: Callahan BP, Miller BG (2007). "OMP decarboxylase--An enigma persists." Bioorg Chem 35(6);465-9. PMID: 17889251

Changeux68: Changeux JP, Gerhart JC, Schachman HK (1968). "Allosteric interactions in aspartate transcarbamylase. I. Binding of specific ligands to the native enzyme and its isolated subunits." Biochemistry 7(2);531-8. PMID: 4868539

Chen89: 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

Chen98: 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

Christopherson78: Christopherson RI, Finch LR (1978). "Response of the pyrimidine pathway of Escherichia coli K 12 to exogenous adenine and uracil." Eur J Biochem 90(2);347-58. PMID: 361403

Coleman77: 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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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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