Asia Kasprzak

Publications (8) View all

• Article: Molecular evolution of dihydrouridine synthases.

  Joanna M Kasprzak, Anna Czerwoniec, Janusz M Bujnicki
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  ABSTRACT: Dihydrouridine (D) is a modified base found in conserved positions in the D-loop of tRNA in Bacteria, Eukaryota, and some Archaea. Despite the abundant occurrence of D, little is known about its biochemical roles in mediating tRNA function. It is assumed that D may destabilize the structure of tRNA and thus enhance its conformational flexibility. D is generated post-transcriptionally by the reduction of the 5,6-double bond of a uridine residue in RNA transcripts. The reaction is carried out by dihydrouridine synthases (DUS). DUS constitute a conserved family of enzymes encoded by the orthologous gene family COG0042. In protein sequence databases, members of COG0042 are typically annotated as "predicted TIM-barrel enzymes, possibly dehydrogenases, nifR3 family". To elucidate sequence-structure-function relationships in the DUS family, a comprehensive bioinformatic analysis was carried out. We performed extensive database searches to identify all members of the currently known DUS family, followed by clustering analysis to subdivide it into subfamilies of closely related sequences. We analyzed phylogenetic distributions of all members of the DUS family and inferred the evolutionary tree, which suggested a scenario for the evolutionary origin of dihydrouridine-forming enzymes. For a human representative of the DUS family, the hDus2 protein suggested as a potential drug target in cancer, we generated a homology model. While this article was under review, a crystal structure of a DUS representative has been published, giving us an opportunity to validate the model. We compared sequences and phylogenetic distributions of all members of the DUS family and inferred the phylogenetic tree, which provides a framework to study the functional differences among these proteins and suggests a scenario for the evolutionary origin of dihydrouridine formation. Our evolutionary and structural classification of the DUS family provides a background to study functional differences among these proteins that will guide experimental analyses.
  BMC Bioinformatics 06/2012; 13:153. · 2.75 Impact Factor
• Source

  Available from: Xavier Lucas

  Article: Virtual screening strategies in drug design – methods and applications Introduction to drug development and design

  Ewa Bielska, Xavier Lucas, Anna Czerwoniec, Joanna M Kasprzak, Katarzyna H Kaminska, Janusz M Bujnicki
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  ABSTRACT: Virtual screening (VS) overcomes the limitations of traditional high-throughput screening (HTS) by applying com-puter-based methods in drug discovery. VS takes advantage of fast algorithms to filter chemical space and success-fully select potential drug candidates. A key aspect in structure-based VS is the sampling of ligand-receptor con-formations and the evaluation of these poses to predict near-native binding modes. The development of fast and accurate algorithms during the last few years has allowed VS to become an important tool in drug discovery and design. Herein, an overview of widely used ligand-based (e.g., similarity, pharmacophore searches) and structure-based (protein-ligand docking) VS methods is discussed. Their strengths and limitations are described, along with many successful stories. This review not only serves as an introductory guide for inexperienced VS users but also presents a general overview of the current state and scope of these powerful tools.
  Biotechnologia 01/2011; 92:249-264.
• Source

  Available from: B. K. C. Patel

  Article: Crystal structure of a fructokinase homolog from Halothermothrix orenii.

  Teck Khiang Chua, J Seetharaman, Joanna M Kasprzak, Cherlyn Ng, Bharat K C Patel, Christopher Love, Janusz M Bujnicki, J Sivaraman
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  ABSTRACT: Fructokinase (FRK; EC 2.7.1.4) catalyzes the phosphorylation of d-fructose to d-fructose 6-phosphate (F6P). This irreversible and near rate-limiting step is a central and regulatory process in plants and bacteria, which channels fructose into a metabolically active state for glycolysis. Towards understanding the mechanism of FRK, here we report the crystal structure of a FRK homolog from a thermohalophilic bacterium Halothermothrixorenii (Hore_18220 in sequence databases). The structure of the Hore_18220 protein reveals a catalytic domain with a Rossmann-like fold and a beta-sheet "lid" for dimerization. Based on comparison of Hore_18220 to structures of related proteins, we propose its mechanism of action, in which the lid serves to regulate access to the substrate binding sites. Close relationship of Hore_18220 and plant FRK enzymes allows us to propose a model for the structure and function of FRKs.
  Journal of Structural Biology 09/2010; 171(3):397-401. · 3.41 Impact Factor
• Chapter: Template Based Prediction of Three‐Dimensional Protein Structures: Fold Recognition and Comparative Modeling

  Jan Kosiński, Karolina L. Tkaczuk, Joanna M. Kasprzak, Janusz M. Bujnicki
  12/2008: pages 87 - 116; , ISBN: 9780470741894
• Source

  Available from: Kristian Rother

  Article: MODOMICS: a database of RNA modification pathways. 2008 update.

  Anna Czerwoniec, Stanislaw Dunin-Horkawicz, Elzbieta Purta, Katarzyna H Kaminska, Joanna M Kasprzak, Janusz M Bujnicki, Henri Grosjean, Kristian Rother
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  ABSTRACT: MODOMICS, a database devoted to the systems biology of RNA modification, has been subjected to substantial improvements. It provides comprehensive information on the chemical structure of modified nucleosides, pathways of their biosynthesis, sequences of RNAs containing these modifications and RNA-modifying enzymes. MODOMICS also provides cross-references to other databases and to literature. In addition to the previously available manually curated tRNA sequences from a few model organisms, we have now included additional tRNAs and rRNAs, and all RNAs with 3D structures in the Nucleic Acid Database, in which modified nucleosides are present. In total, 3460 modified bases in RNA sequences of different organisms have been annotated. New RNA-modifying enzymes have been also added. The current collection of enzymes includes mainly proteins for the model organisms Escherichia coli and Saccharomyces cerevisiae, and is currently being expanded to include proteins from other organisms, in particular Archaea and Homo sapiens. For enzymes with known structures, links are provided to the corresponding Protein Data Bank entries, while for many others homology models have been created. Many new options for database searching and querying have been included. MODOMICS can be accessed at http://genesilico.pl/modomics.
  Nucleic Acids Research 11/2008; 37(Database issue):D118-21. · 8.03 Impact Factor