ArticleProtein science : a publication of the Protein Society1998
The crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A complexed with the enzyme reaction product throws light on its enzymatic function.
Article in Protein science : a publication of the Protein Society, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed.
- Article
- Non-active Site Residue in Loop L4 Alters Substrate Capture and Product Release in d-Arginine Dehydrogenase.Biochemistry · 2023Article
- Class-II dihydroorotate dehydrogenases from three phylogenetically distant fungi support anaerobic pyrimidine biosynthesis.Fungal biology and biotechnology · 2021Article
- New functional families (FunFams) in CATH to improve the mapping of conserved functional sites to 3D structures.Nucleic acids research · 2013Article
- Molecular evolution of dihydrouridine synthases.BMC bioinformatics · 2012Article
- Molecular basis of dihydrouridine formation on tRNA.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Disruption of the proton relay network in the class 2 dihydroorotate dehydrogenase from Escherichia coli.Biochemistry · 2009Article
- Roles in binding and chemistry for conserved active site residues in the class 2 dihydroorotate dehydrogenase from Escherichia coli.Biochemistry · 2009Article
- Contribution of flavin covalent linkage with histidine 99 to the reaction catalyzed by choline oxidase.The Journal of biological chemistry · 2009Article
- Defects in vesicle core induced by escherichia coli dihydroorotate dehydrogenase.Biophysical journal · 2008Article
- Crystallization and preliminary X-ray diffraction analysis of Leishmania major dihydroorotate dehydrogenase.Acta crystallographica. Section F, Structural biology and crystallization communications · 2006Article
- Single-molecule kinetics reveals signatures of half-sites reactivity in dihydroorotate dehydrogenase A catalysis.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
- Catabolite control protein A (CcpA) contributes to virulence and regulation of sugar metabolism in Streptococcus pneumoniae.Journal of bacteriology · 2005Article
- Expression, purification and crystallization of Trypanosoma cruzi dihydroorotate dehydrogenase complexed with orotate.Acta crystallographica. Section F, Structural biology and crystallization communications · 2005Article
- Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain.Protein science : a publication of the Protein Society · 2004Article
- The dimeric dihydroorotate dehydrogenase A from Lactococcus lactis dissociates reversibly into inactive monomers.Protein science : a publication of the Protein Society · 2002Article
- Molecular mimicry of substrate oxygen atoms by water molecules in the beta-amylase active site.Protein science : a publication of the Protein Society · 2001Article
- Eukaryotic beta-alanine synthases are functionally related but have a high degree of structural diversity.Genetics · 2001Article
- Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.The EMBO journal · 2001Article
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Abstract
Dihydroorotate dehydrogenases (DHODs) catalyze the oxidation of (S)-dihydroorotate to orotate, the fourth step and only redox reaction in the de novo biosynthesis of pyrimidine nucleotides. A description is given of the crystal structure of Lactococcus lactis dihydroorotate dehydrogenase A (DHODA) complexed with the product of the enzyme reaction orotate. The structure of the complex to 2.0 A resolution has been compared with the structure of the native enzyme. The active site of DHODA is known to contain a water filled cavity buried beneath a highly conserved and flexible loop. In the complex the orotate displaces the water molecules from the active site and stacks above the DHODA flavin isoalloxazine ring, causing only small movements of the surrounding protein residues. The orotate is completely buried beneath the protein surface, and the orotate binding causes a significant reduction in the mobility of the active site loop. The orotate is bound by four conserved asparagine side chains (Asn 67, Asn 127, Asn 132, and Asn 193), the side chains of Lys 43 and Ser 194, and the main chain NH groups of Met 69, Gly 70, and Leu 71. Of these the Lys 43 side chain makes hydrogen bonds to both the flavin isoalloxazine ring and the carboxylate group of the orotate. Potential interactions with bound dihydroorotate are considered using the orotate complex as a basis for molecular modeling. The role of Cys 130 as the active site base is discussed, and the sequence conservation of the active site residues across the different families of DHODs is reviewed, along with implications for differences in substrate binding and in the catalytic mechanisms between these families.
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