ArticleBioorganic & medicinal chemistry2016
Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase).
Article in Bioorganic & medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- 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
- Bacterial Metallostasis: Metal Sensing, Metalloproteome Remodeling, and Metal Trafficking.Chemical reviews · 2024Review
- Impact of Negative Feedbacks on De Novo Pyrimidines Biosynthesis inInternational journal of molecular sciences · 2023Article
- Crystal Structure of Allantoinase from Escherichia coli BL21: A Molecular Insight into a Role of the Active Site Loops in CatalysisMolecules (Basel, Switzerland) · 2023Article
- Complexed Crystal Structure of the Dihydroorotase Domain of Human CAD Protein with the Anticancer Drug 5-Fluorouracil.Biomolecules · 2023Article
- Article
- Cytotoxic Activities and the Allantoinase Inhibitory Effect of the Leaf Extract of the Carnivorous Pitcher PlantPlants (Basel, Switzerland) · 2022Article
- Anticancer and Antioxidant Activities of the Root Extract of the Carnivorous Pitcher PlantPlants (Basel, Switzerland) · 2022Article
- Structural Analysis ofMolecules (Basel, Switzerland) · 2021Article
- Identification of Small Molecule Inhibitors againstInternational journal of molecular sciences · 2021Article
- Plumbagin, a Natural Product with Potent Anticancer Activities, Binds to and Inhibits Dihydroorotase, a Key Enzyme in Pyrimidine Biosynthesis.International journal of molecular sciences · 2021Article
- Complexed Crystal Structure ofBioinorganic chemistry and applications · 2021Article
- Screening and Molecular Docking of Novel Benzothiazole Derivatives as Potential Antimicrobial Agents.Antibiotics (Basel, Switzerland) · 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
- Characterization of the Dihydroorotase from Methanococcus jannaschii.The protein journal · 2017Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.