10 research outputs found
Structural Diversity and Plasticity Associated with Nucleotides Targeting Orotidine Monophosphate Decarboxylase
Atomic Resolution Structure of the Orotidine 5′-Monophosphate Decarboxylase Product Complex Combined with Surface Plasmon Resonance Analysis
Novel Cytidine-Based Orotidine-5′-Monophosphate Decarboxylase Inhibitors with an Unusual Twist
Orotidine-5′-monophosphate decarboxylase (ODCase)
is an
interesting enzyme with an unusual catalytic activity and a potential
drug target in <i>Plasmodium falciparum</i>, which causes
malaria. ODCase has been shown to exhibit unusual and interesting
interactions with a variety of nucleotide ligands. Cytidine-5′-monophosphate
(CMP) is a poor ligand of ODCase, and CMP binds to the active site
of ODCase with an unusual orientation and conformation. We designed
N3- and N4-modified CMP derivatives as novel ligands to ODCase. These
novel CMP derivatives and their corresponding nucleosides were evaluated
against <i>Plasmodium falciparum</i> ODCase and parasitic
cultures, respectively. These derivatives exhibited improved inhibition
of the enzyme catalytic activity, displayed interesting binding conformations
and unusual molecular rearrangements of the ligands. These findings
with the modified CMP nucleotides underscored the potential of transformation
of poor ligands to ODCase into novel inhibitors of this drug target
G9a selectively represses a class of late-replicating genes at the nuclear periphery
We have investigated the role of the histone methyltransferase G9a in the establishment of silent nuclear compartments. Following conditional knockout of the G9a methyltransferase in mouse ESCs, 167 genes were significantly up-regulated, and no genes were strongly down-regulated. A partially overlapping set of 119 genes were up-regulated after differentiation of G9a-depleted cells to neural precursors. Promoters of these G9a-repressed genes were AT rich and H3K9me2 enriched but H3K4me3 depleted and were not highly DNA methylated. Representative genes were found to be close to the nuclear periphery, which was significantly enriched for G9a-dependent H3K9me2. Strikingly, although 73% of total genes were early replicating, more than 71% of G9a-repressed genes were late replicating, and a strong correlation was found between H3K9me2 and late replication. However, G9a loss did not significantly affect subnuclear position or replication timing of any non-pericentric regions of the genome, nor did it affect programmed changes in replication timing that accompany differentiation. We conclude that G9a is a gatekeeper for a specific set of genes localized within the late replicating nuclear periphery
Orotidine Monophosphate Decarboxylase – A Fascinating Workhorse Enzyme with Therapeutic Potential
Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5′-Monophosphate Decarboxylase
Hydrolytic Mechanism of OXA-58 Enzyme, a Carbapenem-hydrolyzing Class D β-Lactamase from Acinetobacter baumannii
Structures of the Human Orotidine-5′-Monophosphate Decarboxylase Support a Covalent Mechanism and Provide a Framework for Drug Design
Substrate Distortion Contributes to the Catalysis of Orotidine 5′-Monophosphate Decarboxylase
A survey of the year 2006 literature on applications of isothermal titration calorimetry
Isothermal titration calorimetry (ITC) is a fast and robust method to determine the energetics of association reactions in solution. The changes in enthalpy, entropy and heat capacity that accompany binding provide unique insights into the balance of forces driving association of molecular entities. ITC is used nowadays on a day-to-day basis in hundreds of laboratories. The method aids projects both in basic and practice-oriented research ranging from medicine and biochemistry to physical chemistry and material sciences. Not surprisingly, the range of studies utilizing ITC data is steadily expanding. In this review, we discuss selected results and ideas that have accumulated in the course of the year 2006, the focus being on biologically relevant systems. Theoretical developments, novel applications and studies that provide a deeper level of understanding of the energetic principles of biological function are primarily considered. Following the appearance of a new generation of titration calorimeters, recent papers provide instructive examples of the synergy between energetic and structural approaches in biomedical and biotechnological research