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Gerard Parkin - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structures of cadmium carboxylate and thiocarboxylate compounds with a sulfur rich coordination environment carboxylate exchange kinetics involving tris 2 mercapto 1 t butylimidazolyl hydroborato cadmium complexes tmbut cd o2cr
Inorganic Chemistry, 2015Co-Authors: Ava Kreidermueller, Patrick J Quinlivan, Jonathan S Owen, Gerard ParkinAbstract:A series of cadmium carboxylate compounds in a sulfur-rich environment provided by the tris(2-tert-butylmercaptoimidazolyl)hydroborato ligand, namely, [TmBut]CdO2CR, has been synthesized via the reactions of the cadmium methyl derivative [TmBut]CdMe with RCO2H. Such compounds mimic aspects of cadmium-substituted Zinc Enzymes and also the surface atoms of cadmium chalcogenide crystals, and have therefore been employed to model relevant ligand exchange processes. Significantly, both 1H and 19F NMR spectroscopy demonstrate that the exchange of carboxylate groups between [TmBut]Cd(κ2-O2CR) and the carboxylic acid RCO2H is facile on the NMR time scale, even at low temperature. Analysis of the rate of exchange as a function of concentration of RCO2H indicates that reaction occurs via an associative rather than dissociative pathway. In addition to carboxylate compounds, the thiocarboxylate derivative [TmBut]Cd[κ1-SC(O)Ph] has also been synthesized via the reaction of [TmBut]CdMe with thiobenzoic acid. The molecu...
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Synthesis and Structures of Cadmium Carboxylate and Thiocarboxylate Compounds with a Sulfur-Rich Coordination Environment: Carboxylate Exchange Kinetics Involving Tris(2-mercapto-1‑t‑butylimidazolyl)hydroborato Cadmium Complexes, [TmBut]Cd(O2CR)
2015Co-Authors: Ava Kreider-mueller, Patrick J Quinlivan, Jonathan S Owen, Gerard ParkinAbstract:A series of cadmium carboxylate compounds in a sulfur-rich environment provided by the tris(2-tert-butylmercaptoimidazolyl)hydroborato ligand, namely, [TmBut]CdO2CR, has been synthesized via the reactions of the cadmium methyl derivative [TmBut]CdMe with RCO2H. Such compounds mimic aspects of cadmium-substituted Zinc Enzymes and also the surface atoms of cadmium chalcogenide crystals, and have therefore been employed to model relevant ligand exchange processes. Significantly, both 1H and 19F NMR spectroscopy demonstrate that the exchange of carboxylate groups between [TmBut]Cd(κ2-O2CR) and the carboxylic acid RCO2H is facile on the NMR time scale, even at low temperature. Analysis of the rate of exchange as a function of concentration of RCO2H indicates that reaction occurs via an associative rather than dissociative pathway. In addition to carboxylate compounds, the thiocarboxylate derivative [TmBut]Cd[κ1-SC(O)Ph] has also been synthesized via the reaction of [TmBut]CdMe with thiobenzoic acid. The molecular structure of [TmBut]Cd[κ1-SC(O)Ph] has been determined by X-ray diffraction, and an interesting feature is that, in contrast to the carboxylate derivatives [TmBut]Cd(κ2-O2CR), the thiocarboxylate ligand binds in a κ1 manner via only the sulfur atom
Claudiu T Supuran - One of the best experts on this subject based on the ideXlab platform.
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biochemical characterization of the chloroplastic β carbonic anhydrase from flaveria bidentis l kuntze
Journal of Enzyme Inhibition and Medicinal Chemistry, 2014Co-Authors: Nina A Dathan, Claudiu T Supuran, Daniela Vullo, Vincenzo Alterio, Elisa Troiano, Martha Ludwig, Giuseppina De Simone, Simona Maria MontiAbstract:AbstractC3 and C4 plant carbonic anhydrases (CAs) are Zinc-Enzymes that catalyze the reversible hydration of CO2. They are sub-divided in three classes: α, β and γ, being distributed between both photosynthetic subtypes. The C4 dicotyledon species Flaveria bidentis (L.) “Kuntze” contains a small gene family encoding three distinct β-CAs, named FbiCA1, FbiCA2 and FbiCA3. We have expressed and purified recombinant FbiCA1, which is localized in the chloroplast where it is thought to play a role in lipid biosynthesis and antioxidant activity, and biochemically characterized it by spectroscopic and inhibition experiments. FbiCA1 is a compact octameric protein that is moderately inhibited by carboxylate molecules. Surprisingly, pyruvate, but not lactate, did not inhibit FbiCA1 at concentrations up to 10 mM, suggesting that its capacity to tolerate high pyruvate concentration reflects the high concentration of pyruvate in the chloroplasts of bundle-sheath and mesophyll cells involved in C4 photosynthesis.
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the alpha carbonic anhydrase from the thermophilic bacterium sulfurihydrogenibium yellowstonense yo3aop1 is highly susceptible to inhibition by sulfonamides
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Daniela Vullo, Claudiu T Supuran, Viviana De Luca, Andrea Scozzafava, Vincenzo Carginale, Mose Rossi, Clemente CapassoAbstract:Abstract The α-carbonic anhydrase (CA, EC 4.2.1.1) from the newly discovered thermophilic bacterium Sulfurihydrogenibium yellowstonense YO3AOP1 (SspCA) was investigated for its inhibition with a large series of sulfonamides and a sulfamate, the classical inhibitors of these Zinc Enzymes. SspCA showed an inhibition profile with these compounds very similar to that of the predominant human cytosolic isoform hCA II, and not to that of the bacterial α-CA from Helicobacter pylori . Some clinically used drugs such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, celecoxib and sulthiame were low nanomolar SspCA/hCA II inhibitors (K I s in the range of 4.5–12.3 nM) whereas simple aromatic/heterocyclic sulfonamides were less effective, micromolar inhibitors. As this highly catalytically active and thermostable enzyme may show biotechnological applications, its inhibition studies may be relevant for designing on/off systems to control its activity.
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nanoscale enzyme inhibitors fullerenes inhibit carbonic anhydrase by occluding the active site entrance
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Alessio Innocenti, Amanda T Strom, Nadjmeh Doostdar, Serdar Durdagi, Andrew R. Barron, Claudiu T SupuranAbstract:Abstract We investigated a series of derivatized fullerenes possessing alcohol, amine, and amino acid pendant groups as inhibitors of the Zinc Enzymes carbonic anhydrases (CAs, EC 4.2.1.1). We discovered that fullerenes bind CAs with submicromolar—low micromolar affinity, despite the fact that these compounds do not possess moieties normally associated with CA inhibitors such as the sulfonamides and their isosteres, or the coumarins. The 13 different mammalian CA isoforms showed a diverse inhibition profile with these compounds. By means of computational methods we assessed the inhibition mechanism as being due to occlusion of the active site entrance by means of the fullerene cage (possessing dimension of the same order of magnitude as the opening of the enzyme cavity, of 1 nm). The pendant moieties to the fullerene cage make interactions with amino acid residues from the active site, among which His64, His94, His96, Val121, and Thr200. Fullerenes thus represent a totally new class of nanoscale CA inhibitors which may show applications for targeting physiologically relevant isoforms, such as the dominant CA II and the tumor-associated CA IX.
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nanoscale enzyme inhibitors fullerenes inhibit carbonic anhydrase by occluding the active site entrance
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Alessio Innocenti, Amanda T Strom, Nadjmeh Doostdar, Serdar Durdagi, Andrew R. Barron, Claudiu T SupuranAbstract:Abstract We investigated a series of derivatized fullerenes possessing alcohol, amine, and amino acid pendant groups as inhibitors of the Zinc Enzymes carbonic anhydrases (CAs, EC 4.2.1.1). We discovered that fullerenes bind CAs with submicromolar—low micromolar affinity, despite the fact that these compounds do not possess moieties normally associated with CA inhibitors such as the sulfonamides and their isosteres, or the coumarins. The 13 different mammalian CA isoforms showed a diverse inhibition profile with these compounds. By means of computational methods we assessed the inhibition mechanism as being due to occlusion of the active site entrance by means of the fullerene cage (possessing dimension of the same order of magnitude as the opening of the enzyme cavity, of 1 nm). The pendant moieties to the fullerene cage make interactions with amino acid residues from the active site, among which His64, His94, His96, Val121, and Thr200. Fullerenes thus represent a totally new class of nanoscale CA inhibitors which may show applications for targeting physiologically relevant isoforms, such as the dominant CA II and the tumor-associated CA IX.
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therapeutic applications of glycosidic carbonic anhydrase inhibitors
ChemInform, 2009Co-Authors: Jeanyves Winum, Sallyann Poulsen, Claudiu T SupuranAbstract:The Zinc Enzymes carbonic anhydrases (CAs, EC 4.2.1.1) are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and hence play an important physiological role. In humans, 16 different isozymes have been described, some of them being involved in various pathological disorders. Several of these isozymes are considered as drug targets, and the design of selective inhibitors is a long-standing goal that has captured the attention of researchers for 40 years and has lead to clinical applications against different pathologies such as glaucoma, epilepsy, and cancer. Among the different strategies developed for designing selective CA inhibitors (CAIs), the "sugar approach" has recently emerged as a new attractive and versatile tool. Incorporation of glycosyl moieties in different aromatic/heterocyclic sulfonamide/sulfamides/sulfamates scaffolds has led to the development of numerous and very effective inhibitors of potential clinical value. The clinical use of a highly active carbohydrate-based CA inhibitor, i.e., topiramate, constitutes an interesting demonstration of the validity of this approach. Other carbohydrate-based compounds also demonstrate promising potential for the treatment of ophthalmologic diseases. This review will focus on the development of this emerging sugar-based approach for the development of CAIs.
Kenton R Rodgers - One of the best experts on this subject based on the ideXlab platform.
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methanethiol binding strengths and deprotonation energies in zn ii imidazole complexes from m05 2x and mp2 theories coordination number and geometry influences relevant to Zinc Enzymes
Journal of Physical Chemistry B, 2015Co-Authors: Douglas P Linder, Kenton R RodgersAbstract:Zn(II) is used in nature as a biocatalyst in hundreds of Enzymes, and the structure and dynamics of its catalytic activity are subjects of considerable interest. Many of the Zn(II)-based Enzymes are classified as hydrolytic Enzymes, in which the Lewis acidic Zn(II) center facilitates proton transfer(s) to a Lewis base, from proton donors such as water or thiol. This report presents the results of a quantum computational study quantifying the dynamic relationship between the Zinc coordination number (CN), its coordination geometry, and the thermodynamic driving force behind these proton transfers originating from a charge-neutral methylthiol ligand. Specifically, density functional theory (DFT) and second-order perturbation theory (MP2) calculations have been performed on a series of [(imidazole)nZn–S(H)CH3]2+ and [(imidazole)nZn–SCH3]+ complexes with the CN varied from 1 to 6, n = 0–5. As the number of imidazole ligands coordinated to Zinc increases, the S–H proton dissociation energy also increases, (i.e...
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methanethiol binding strengths and deprotonation energies in zn ii imidazole complexes from m05 2x and mp2 theories coordination number and geometry influences relevant to Zinc Enzymes
The Journal of Physical Chemistry, 2015Co-Authors: Douglas P Linder, Kenton R RodgersAbstract:Zn(II) is used in nature as a biocatalyst in hundreds of Enzymes, and the structure and dynamics of its catalytic activity are subjects of considerable interest. Many of the Zn(II)-based Enzymes are classified as hydrolytic Enzymes, in which the Lewis acidic Zn(II) center facilitates proton transfer(s) to a Lewis base, from proton donors such as water or thiol. This report presents the results of a quantum computational study quantifying the dynamic relationship between the Zinc coordination number (CN), its coordination geometry, and the thermodynamic driving force behind these proton transfers originating from a charge-neutral methylthiol ligand. Specifically, density functional theory (DFT) and second-order perturbation theory (MP2) calculations have been performed on a series of [(imidazole)ₙZn–S(H)CH₃]²⁺ and [(imidazole)ₙZn–SCH₃]⁺ complexes with the CN varied from 1 to 6, n = 0–5. As the number of imidazole ligands coordinated to Zinc increases, the S–H proton dissociation energy also increases, (i.e., −S(H)CH₃ becomes less acidic), and the Zn–S bond energy decreases. Furthermore, at a constant CN, the S–H proton dissociation energy decreases as the S–Zn–(ImH)ₙ angles increase about their equilibrium position. The Zinc-coordinated thiol can become more or less acidic depending upon the position of the coordinated imidazole ligands. The bonding and thermodynamic relationships discussed may apply to larger systems that utilize the [(His)₃Zn(II)–L] complex as the catalytic site, including carbonic anhydrase, carboxypeptidase, β-lactamase, the tumor necrosis factor-α-converting enzyme, and the matrix metalloproteinases.
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Methanethiol Binding Strengths and Deprotonation Energies in Zn(II)–Imidazole Complexes from M05-2X and MP2 Theories: Coordination Number and Geometry Influences Relevant to Zinc Enzymes
2015Co-Authors: Douglas P Linder, Kenton R RodgersAbstract:Zn(II) is used in nature as a biocatalyst in hundreds of Enzymes, and the structure and dynamics of its catalytic activity are subjects of considerable interest. Many of the Zn(II)-based Enzymes are classified as hydrolytic Enzymes, in which the Lewis acidic Zn(II) center facilitates proton transfer(s) to a Lewis base, from proton donors such as water or thiol. This report presents the results of a quantum computational study quantifying the dynamic relationship between the Zinc coordination number (CN), its coordination geometry, and the thermodynamic driving force behind these proton transfers originating from a charge-neutral methylthiol ligand. Specifically, density functional theory (DFT) and second-order perturbation theory (MP2) calculations have been performed on a series of [(imidazole)nZn–S(H)CH3]2+ and [(imidazole)nZn–SCH3]+ complexes with the CN varied from 1 to 6, n = 0–5. As the number of imidazole ligands coordinated to Zinc increases, the S–H proton dissociation energy also increases, (i.e., −S(H)CH3 becomes less acidic), and the Zn–S bond energy decreases. Furthermore, at a constant CN, the S–H proton dissociation energy decreases as the S–Zn–(ImH)n angles increase about their equilibrium position. The Zinc-coordinated thiol can become more or less acidic depending upon the position of the coordinated imidazole ligands. The bonding and thermodynamic relationships discussed may apply to larger systems that utilize the [(His)3Zn(II)–L] complex as the catalytic site, including carbonic anhydrase, carboxypeptidase, β-lactamase, the tumor necrosis factor-α-converting enzyme, and the matrix metalloproteinases
Wolfgang Maret - One of the best experts on this subject based on the ideXlab platform.
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picomolar concentrations of free Zinc ii ions regulate receptor protein tyrosine phosphatase β activity
Journal of Biological Chemistry, 2012Co-Authors: Matthew Wilson, Christer Hogstrand, Wolfgang MaretAbstract:As key Enzymes in the regulation of biological phosphorylations, protein-tyrosine phosphatases are central to the control of cellular signaling and metabolism. Zinc(II) ions are known to inhibit these Enzymes, but the physiological significance of this inhibition has remained elusive. Employing metal buffering for strict metal control and performing a kinetic analysis, we now demonstrate that Zinc(II) ions are reversible inhibitors of the cytoplasmic catalytic domain of the receptor protein-tyrosine phosphatase β (also known as vascular endothelial protein-tyrosine phosphatase). The K(i)((Zn)) value is 21 ± 7 pm, 6 orders of magnitude lower than Zinc inhibition reported previously for this enzyme. It exceeds the affinity of the most potent synthetic small molecule inhibitors targeting these Enzymes. Inhibition is in the range of cellular Zinc(II) ion concentrations, suggesting that Zinc regulates this enzyme, which is involved in vascular physiology and angiogenesis. Thus, for some Enzymes that are not recognized as Zinc metalloEnzymes, Zinc binding inhibits rather than activates as in classical Zinc Enzymes. Activation then requires removal of the inhibitory Zinc.
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thionein metallothionein control zn ii availability and the activity of Enzymes
Journal of Biological Inorganic Chemistry, 2008Co-Authors: Artur Krezel, Wolfgang MaretAbstract:Fundamental issues in Zinc biology are how proteins control the concentrations of free Zn(II) ions and how tightly they interact with them. Since, basically, the Zn(II) stability constants of only two cytosolic Zinc Enzymes, carbonic anhydrase and superoxide dismutase, have been reported, the affinity for Zn(II) of another Zinc enzyme, sorbitol dehydrogenase (SDH), was determined. Its log K is 11.2 ± 0.1, which is similar to the log K values of carbonic anhydrase and superoxide dismutase despite considerable differences in the coordination environments of Zn(II) in these Enzymes. Protein tyrosine phosphatase 1B (PTP 1B), on the other hand, is not classified as a Zinc enzyme but is strongly inhibited by Zn(II), with log K = 7.8 ± 0.1. In order to test whether or not metallothionein (MT) can serve as a source for Zn(II) ions, it was used to control free Zn(II) ion concentrations. MT makes Zn(II) available for both PTP 1B and the apoform of SDH. However, whether or not Zn(II) ions are indeed available for interaction with these Enzymes depends on the thionein (T) to MT ratio and the redox poise. At ratios [T/(MT + T) = 0.08–0.31] prevailing in tissues and cells, picomolar concentrations of free Zn(II) are available from MT for reconstituting apoEnzymes with Zn(II). Under conditions of decreased ratios, nanomolar concentrations of free Zn(II) become available and affect Enzymes that are not Zinc metalloEnzymes. The match between the Zn(II) buffering capacity of MT and the Zn(II) affinity of proteins suggests a function of MT in controlling cellular Zn(II) availability.
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the function of Zinc metallothionein a link between cellular Zinc and redox state
Journal of Nutrition, 2000Co-Authors: Wolfgang MaretAbstract:A chemical and biochemical mechanism of action of the metallothionein (MT)/thionein (T) couple has been proposed. The mechanism emphasizes the importance of Zinc/sulfur cluster bonding in MT and the significance of the two cluster networks as redox units that confer mobility on otherwise tightly bound and redox-inert Zinc in MT. In this article, it is further explored how this redox mechanism controls the metabolically active cellular Zinc pool. The low redox potential of the sulfur donor atoms in the clusters readily allows oxidation by mild cellular oxidants with concomitant release of Zinc. Such a release by oxidants and the preservation of Zinc binding by antioxidants place MT under the control of the cellular redox state and, consequently, energy metabolism. The binding of effectors, e.g., ATP, elicits conformational changes and alters Zinc binding in MT. The glutathione/glutathione disulfide redox couple as well as selenium compounds effect Zinc delivery from MT to the apoforms of Zinc Enzymes. This novel action of selenium on Zinc/sulfur coordination sites has significant implications for the interaction between these essential elements. Tight binding and kinetic lability, modulation of MT by cellular ligands and the redox state, control of MT gene expression by Zinc and many other inducers all support a critical function of the MT/T system in cellular homeostasis and distribution of Zinc.
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Control of Zinc transfer between thionein, metallothionein, and Zinc proteins
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Claus Jacob, Wolfgang Maret, Bert L. ValleeAbstract:Metallothionein (MT), despite its high metal binding constant (KZn = 3.2 × 1013 M−1 at pH 7.4), can transfer Zinc to the apoforms of Zinc Enzymes that have inherently lower stability constants. To gain insight into this paradox, we have studied Zinc transfer between Zinc Enzymes and MT. Zinc can be transferred in both directions—i.e., from the Enzymes to thionein (the apoform of MT) and from MT to the apoEnzymes. Agents that mediate or enhance Zinc transfer have been identified that provide kinetic pathways in either direction. MT does not transfer all of its seven Zinc atoms to an apoenzyme, but apparently contains at least one that is more prone to transfer than the others. Modification of thiol ligands in MT Zinc clusters increases the total number of Zinc ions released and, hence, the extent of transfer. Aside from disulfide reagents, we show that selenium compounds are potential cellular enhancers of Zinc transfer from MT to apoEnzymes. Zinc transfer from Zinc Enzymes to thionein, on the other hand, is mediated by Zinc-chelating agents such as Tris buffer, citrate, or glutathione. Redox agents are asymmetrically involved in both directions of Zinc transfer. For example, reduced glutathione mediates Zinc transfer from Enzymes to thionein, whereas glutathione disulfide oxidizes MT with enhanced release of Zinc and transfer of Zinc to apoEnzymes. Therefore, the cellular redox state as well as the concentration of other biological chelating agents might well determine the direction of Zinc transfer and ultimately affect Zinc distribution.
Ava Kreidermueller - One of the best experts on this subject based on the ideXlab platform.
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synthesis and structures of cadmium carboxylate and thiocarboxylate compounds with a sulfur rich coordination environment carboxylate exchange kinetics involving tris 2 mercapto 1 t butylimidazolyl hydroborato cadmium complexes tmbut cd o2cr
Inorganic Chemistry, 2015Co-Authors: Ava Kreidermueller, Patrick J Quinlivan, Jonathan S Owen, Gerard ParkinAbstract:A series of cadmium carboxylate compounds in a sulfur-rich environment provided by the tris(2-tert-butylmercaptoimidazolyl)hydroborato ligand, namely, [TmBut]CdO2CR, has been synthesized via the reactions of the cadmium methyl derivative [TmBut]CdMe with RCO2H. Such compounds mimic aspects of cadmium-substituted Zinc Enzymes and also the surface atoms of cadmium chalcogenide crystals, and have therefore been employed to model relevant ligand exchange processes. Significantly, both 1H and 19F NMR spectroscopy demonstrate that the exchange of carboxylate groups between [TmBut]Cd(κ2-O2CR) and the carboxylic acid RCO2H is facile on the NMR time scale, even at low temperature. Analysis of the rate of exchange as a function of concentration of RCO2H indicates that reaction occurs via an associative rather than dissociative pathway. In addition to carboxylate compounds, the thiocarboxylate derivative [TmBut]Cd[κ1-SC(O)Ph] has also been synthesized via the reaction of [TmBut]CdMe with thiobenzoic acid. The molecu...
