ArticleBiochemistry2009
Dihydroorotase from the hyperthermophile Aquifex aeolicus is activated by stoichiometric association with aspartate transcarbamoylase and forms a one-pot reactor for pyrimidine biosynthesis.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 40 citations in OpenAlex.
- Crystallographic snapshots of Trypanosoma cruzi aspartate transcarbamoylase including catalytic intermediates suggest an ordered Bi-Bi reaction mechanism.Scientific reports · 2026Article
- Crystal structure of Methanococcus jannaschii dihydroorotase with substrate bound.Acta crystallographica. Section F, Structural biology communications · 2026Article
- Conformational Dynamics of the Active Site Loop in Dihydroorotase Highlighting the Limitations of Loop-In Structures for Inhibitor Docking.International journal of molecular sciences · 2025Article
- The Loop-In Binding Mode of Dihydroorotase: Implications for Ligand Binding and Therapeutic Targeting.International journal of molecular sciences · 2025Review
- Article
- Structural analysis and molecular substrate recognition properties ofFrontiers in plant science · 2023Article
- Deciphering CAD: Structure and function of a mega-enzymatic pyrimidine factory in health and disease.Protein science : a publication of the Protein Society · 2021Review
- Characterization and assembly of the Pseudomonas aeruginosa aspartate transcarbamoylase-pseudo dihydroorotase complex.PloS one · 2020Article
- Pyrimidine biosynthesis in pathogens - Structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae.International journal of biological macromolecules · 2019Article
- Characterization of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD.The Journal of biological chemistry · 2018Article
- Sources and Fates of Carbamyl Phosphate: A Labile Energy-Rich Molecule with Multiple Facets.Biology · 2018Review
- Characterization of the Dihydroorotase from Methanococcus jannaschii.The protein journal · 2017Article
- Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks.PLoS computational biology · 2017Article
- Activation of Latent Dihydroorotase from Aquifex aeolicus by Pressure.The Journal of biological chemistry · 2017Article
- From Genome to Structure and Back Again: A Family Portrait of the Transcarbamylases.International journal of molecular sciences · 2015Review
- Intersubunit communication in the dihydroorotase-aspartate transcarbamoylase complex of Aquifex aeolicus.Protein science : a publication of the Protein Society · 2014Article
- The mononuclear metal center of type-I dihydroorotase from Aquifex aeolicus.BMC biochemistry · 2013Article
- Expression, purification, crystallization and preliminary X-ray diffraction analysis of the aspartate transcarbamoylase domain of human CAD.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Evolution of cyclic amidohydrolases: a highly diversified superfamily.Journal of molecular evolution · 2013Article
- Expression, purification, crystallization and preliminary X-ray diffraction analysis of the dihydroorotase domain of human CAD.Acta crystallographica. Section F, Structural biology and crystallization communications · 2012Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
In prokaryotes, the first three enzymes in pyrimidine biosynthesis, carbamoyl phosphate synthetase (CPS), aspartate transcarbamoylase (ATC), and dihydroorotase (DHO), are commonly expressed separately and either function independently (Escherichia coli) or associate into multifunctional complexes (Aquifex aeolicus). In mammals the enzymes are expressed as a single polypeptide chain (CAD) in the order CPS-DHO-ATC and associate into a hexamer. This study presents the three-dimensional structure of the noncovalent hexamer of DHO and ATC from the hyperthermophile A. aeolicus at 2.3 A resolution. It is the first structure of any multienzyme complex in pyrimidine biosynthesis and is a possible model for the core of mammalian CAD. The structure has citrate, a near isosteric analogue of carbamoyl aspartate, bound to the active sites of both enzymes. Three active site loops that are intrinsically disordered in the free, inactive DHO are ordered in the complex. The reorganization also changes the peptide bond between Asp153, a ligand of the single zinc atom in DHO, and Gly154, to the rare cis conformation. In the crystal structure, six DHO and six ATC chains form a hollow dodecamer, in which the 12 active sites face an internal reaction chamber that is approximately 60 A in diameter and connected to the cytosol by narrow tunnels. The entrances and the interior of the chamber are both electropositive, which suggests that the architecture of this nanoreactor modifies the kinetics of the bisynthase, not only by steric channeling but also by preferential escape of the product, dihydroorotase, which is less negatively charged than its precursors, carbamoyl phosphate, aspartate, or carbamoyl aspartate.
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