If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
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 nucleotides are components of nucleic acids in all living organisms. Although the enzymatic steps in their de novo biosynthesis are conserved, some differences in the enzymes exist. For example in bacteria and plants the three steps leading from carbamoyl phosphate to orotate are catalyzed by three different proteins, while in mammals they are catalyzed by a single multifunctional CAD protein. In plants and animals the last two steps of the pathway are catalyzed by the bifunctional enzyme UMP synthase, whereas bacteria express two separate proteins for this purpose (in [Iwahana96, Giermann02] and reviewed in [Zrenner06].
About This Pathway
The de novo pyrimidine nucleotide biosynthetic pathway converts bicarbonate, L-glutamine, L-aspartate and 5-phospho-α-D-ribose 1-diphosphate (PRPP) to uridine 5'-phosphate (UMP), a pyrimidine ribonucleotide that can be subsequently converted to other pyrimidine ribonucleotides as shown in the link at the end of this pathway, and in the superpathway links below.
The first enzyme, carbamoyl phosphate synthetase, forms carbamoyl phosphate from ATP, bicarbonate, and ammonia derived from L-glutamine. Carbamoyl phosphate is both an intermediate of pyrimidine synthesis and also a precursor for the synthesis of amino acids such as L-arginine and L-citrulline as shown in the pathway link, and L-canavanine in plants [Cronk06].
The next step, which is catalyzed by aspartate transcarbamylase, is the condensation of carbamoyl phosphate with L-aspartate forming N-carbamoyl-L-aspartate. This is the committed step in pyrimidine nucleotide biosynthesis. N-carbamoyl-L-aspartate, is then cyclized to (S)-dihydroorotate, the first intermediate that contains a pyrimidine ring. This compound is oxidized to orotate by dihydroorotate dehydrogenase. Orotate, an aromatic pyrimidine base, is therefore formed in three steps from carbamoyl phosphate.
The final two steps, the condensation of orotate with PRPP forming the first pyrimidine nucleotide 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. UMP was identified in early work as an inhibitor of the first enzyme carbamoyl phosphate synthase [Trotta74].
In enteric bacteria the pyrimidine biosynthetic genes are scattered on the chromosome and may be a single transcriptional unit or part of a small operon. They have their own regulatory mechanisms and are not regulated by a common repressor.
Review: Jensen, K.F., G. Dandanell, B. Hove-Jensen and M. Willemoes (2008) "Nucleotides, Nucleosides and Nucleobases" EcoSal 3.6.2 [ECOSAL]
Superpathways: superpathway of pyrimidine ribonucleotides de novo biosynthesis, superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis, superpathway of histidine, purine, and pyrimidine biosynthesis
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
Last-Curated 03-Jun-2011 by Fulcher C, SRI International
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
Trotta74: Trotta PP, Pinkus LM, Haschemeyer RH, Meister A (1974). "Reversible dissociation of the monomer of glutamine-dependent carbamyl phosphate synthetase into catalytically active heavy and light subunits." J Biol Chem 1974;249(2);492-9. PMID: 4358555
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
Alam04a: 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
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
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
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
Bjornberg01: Bjornberg O, Jordan DB, Palfey BA, Jensen KF (2001). "Dihydrooxonate is a substrate of dihydroorotate dehydrogenase (DHOD) providing evidence for involvement of cysteine and serine residues in base catalysis." Arch Biochem Biophys 391(2);286-94. PMID: 11437361
Bjornberg99: Bjornberg O, Gruner AC, Roepstorff P, Jensen KF (1999). "The activity of Escherichia coli dihydroorotate dehydrogenase is dependent on a conserved loop identified by sequence homology, mutagenesis, and limited proteolysis." Biochemistry 38(10);2899-908. PMID: 10074342
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
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
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
Showing only 20 references. To show more, press the button "Show all references".
©2015 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493