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Joseph A Beavo - One of the best experts on this subject based on the ideXlab platform.
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Cyclic Nucleotide Phosphodiesterases in Health and Disease - Cyclic Nucleotide Phosphodiesterases in Health and Disease
2006Co-Authors: Joseph A Beavo, Sharron H. Francis, Miles D HouslayAbstract:Cyclic Nucleotide Phosphodiesterase Superfamily, J. A. Beavo, M. D. Houslay, and S. H. Francis Phosphodiesterase Isoforms-An Annotated List, G. B. Bolger Section A Specific Phosphodiesterase Families-Regulation, Molecular and Biochemical Characteristics Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterases, A. T. Bender PDE2 Structure and Functions, S. E. Martinez Phosphodiesterase 3B: An Important Regulator of Energy Homeostasis, E. Degerman and V. Manganiello Cellular Functions of PDE4 Enzymes, G. B. Bolger, M. Conti, and M. D. Houslay Phosphodiesterase 5: Molecular Characteristics Relating to Structure, Function, and Regulation, S. H. Francis, R. Zoraghi, J. Kotera, H. Ke, E. P. Bessay, M. A. Blount, and J. D. Corbin Photoreceptor Phosphodiesterase (PDE6): A G-Protein-Activated PDE Regulating Visual Excitation in Rod and Cone Photoreceptor Cells, R. H. Cote PDE7, T. Michaeli cAMP-Phosphodiesterase PDE 8 , V. Vasta PDE9, J. Kotera and K. Omori PDE10A: A Striatum Enriched, Dual-Substrate Phosphodiesterase, C. A. Strick, C. J. Schmidt, and F. S. Menniti PDE11, K. Omori and J. Kotera Section B Nonmammalian Phosphodiesterases Protozoal Phosphodiesterases, L.Wentzinger and T. Seebeck Studies of Phosphodiesterase Function Using Fruit Fly Genomics and Transgenics, S. A. Davies and J. P. Day Section C Phosphodiesterases Functional Significance: Gene-Targeted Knockout Strategies Insights into the Physiological Functions of PDE4 from Knockout Mice, S. L. C. Jin, W. Richter, and M. Conti Regulation of cAMP Level by PDE3B-Physiological Implications in Energy Balance and Insulin Secretion, A. Z. Zhao and L. Stenson Holst Section D Compartmentation in Cyclic Nucleotide Signaling Heart Failure, Fibrosis, and Cyclic Nucleotide Metabolism in Cardiac Fibroblasts, S. A. Epperson and L. L. Brunton Role of A-Kinase Anchoring Proteins in the Compartmentation in Cyclic Nucleotide Signaling, O. Witczak, E. M. Aandahl, and K. Tasken Role of Phosphodiesterases in Cyclic Nucleotide Compartmentation in Cardiac Myocytes, A. Abi-Gerges, L. R.V. Castro, F. Rochais, G. Vandecasteele, and R. Fischmeister Section E Phosphodiesterases as Pharmacological Targets in Disease Processes Role of PDEs in Vascular Health and Disease: Endothelial PDEs and Angiogenesis, T. Keravis, A. P. Silva, L. Favot, and C. Lugnier Regulation of PDE Expression in Arteries: Role in Controlling Vascular Cyclic Nucleotide Signaling, D. H. Maurice and D. G. Tilley Regulation and Function of Cyclic Nucleotide Phosphodiesterases in Vascular Smooth Muscle and Vascular Diseases, C. Yan, D. J. Nagel, and K. Jeon Role of Cyclic Nucleotide Phosphodiesterases in Heart Failure and Hypertension, M. A. Movsesian and C. J. Smith Molecular Determinants in Pulmonary Hypertension: The Role of PDE5, N.J. Pyne, F. Murray, R. Tate, and M.R. MacLean Role of PDE5 in Migraine, C. Kruuse Phosphodiesterase-4 as a Pharmacological Target Mediating Antidepressant and Cognitive Effects on Behavior, H. T. Zhang and J. M. O'Donnell Role of Phosphodiesterases in Apoptosis, A. Lerner, E. Y.Moon, and S. Tiwari Section F Development of Specific Phosphodiesterase Inhibitors as Therapeutic Agents Crystal Structure of Phosphodiesterase Families and the Potential for Rational Drug Design, K. Y. J. Zhang Structure, Catalytic Mechanism, and Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases, H. Ke and H. Wang Bench to Bedside: Multiple Actions of the PDE3 Inhibitor Cilostazol, J. Kambayashi, Y. Shakur, and Y. Liu Reinventing the Wheel: Nonselective Phosphodiesterase Inhibitors for Chronic Inflammatory Diseases, M. A. Giembycz Medicinal Chemistry of PDE4 Inhibitors, J. M. McKenna and G. W. Muller Index
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Solubilization of Membrane-bound Rod Phosphodiesterase by the Rod Phosphodiesterase Recombinant δ Subunit
Journal of Biological Chemistry, 1996Co-Authors: Stephanie K. Florio, Rabi K. Prusti, Joseph A BeavoAbstract:Abstract Retinal rod and cone Phosphodiesterases are oligomeric enzymes that consist of a dimeric catalytic core (α′2 in cones and αβ in rods) with inhibitory subunits (γ) that regulate their activity. In addition, a 17-kDa protein referred to as the δ subunit co-purifies with the rod soluble Phosphodiesterase and the cone Phosphodiesterase. We report here partial protein sequencing of the rod δ subunit and isolation of a cDNA clone encoding it. The predicted amino acid sequence is unrelated to any other known protein. Of eight bovine tissue mRNA preparations examined by Northern analysis, the strongest δ subunit-specific signal was present in the retina. A less intense signal was seen in the brain and adrenal mRNA. In bovine retinal sections, rod δ subunit anti-peptide antibodies label rod but not cone outer segments. δ subunit, added back to washed outer segment membranes, solubilizes a large fraction of the membrane-bound Phosphodiesterase, indicating that this subunit binds to the classical membrane associated Phosphodiesterase. The subunit forms a tight complex with native, but not trypsin-released Phosphodiesterase, suggesting that the isoprenylated carboxyl termini of the catalytic subunits may be involved in binding of the δ subunit to the Phosphodiesterase holoenzyme.
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and Cellular Biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joseph A BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-nhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity. (Mol Cell Biochem 127/128: 239–253, 1993)
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primary sequence of cyclic nucleotide Phosphodiesterase isozymes and the design of selective inhibitors
Trends in Pharmacological Sciences, 1990Co-Authors: Joseph A Beavo, David H ReifsnyderAbstract:Primary sequence information has been reported for more than 15 different mammalian cyclic nucleotide Phosphodiesterases. Moreover, recent observations suggest that many of these isozymes are selectively expressed in a limited number of cell types. The fact that nearly all these different Phosphodiesterases have unique primary sequences in their catalytic or regulatory domains and that they are often selectively expressed implies that it may be possible to modulate individual isozymes using specific drugs. Joe Beavo and David Reifsnyder summarize much of the evidence that has led to our current understanding of multiple isozymes of Phosphodiesterase, with emphasis on aspects that may be relevant to drug design. They also discuss why many previous attempts to isolate isozyme-selective inhibitors may have failed.
Joe Beavo - One of the best experts on this subject based on the ideXlab platform.
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cyclic nucleotide Phosphodiesterases functional implications of multiple isoforms
Physical Review, 1995Co-Authors: Joe BeavoAbstract:In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide Phosphodiesterases. In particular, the accumulating data showing that there are a large number of different Phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide Phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of Phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual Phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct Phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and cellular biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joe BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-inhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity.
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cyclic nucleotide Phosphodiesterases structure regulation and drug action
1990Co-Authors: Joe Beavo, Miles D HouslayAbstract:Partial table of contents: SPECIFIC FORMS OF CYCLIC NUCLEOTIDE PhosphodiesteraseS. Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterases (J. Wang, et al.). Cyclic GMP-Inhibited Cyclic Nucleotide Phosphodiesterases (V. Manganiello, et al.). Cyclic CMP-Specific Phosphodiesterase Activity (R. Newton, et al.). ANALYSES OF Phosphodiesterase FORMS AND THEIR FUNCTION IN SPECIFIC CELLULAR SYSTEMS. Phosphodiesterases in Visual Transduction by Rods and Cones (P. Gillespie). STRUCTURAL AND FUNCTIONAL ANALYSES OF PhosphodiesteraseS USING MOLECULAR BIOLOGICAL TECHNIQUES. Molecular Genetics of the Cyclic Nucleotide Phosphodiesterases (R. Davis). Structure and Function of the Rolipram-Sensitive, Low Km Cyclic AMP Phosphodiesterases: A Family of Highly Related Enzymes (M. Conti & J. Swinnen). DEVELOPMENT OF SELECTIVE INHIBITORS OF CYCLIC NUCLEOTIDE PhosphodiesteraseS AS THERAPEUTIC AGENTS. Cardiac Phosphodiesterases and the Functional Effects of Selective Inhibition (M. Reeves & P. Englund). Second Generation Phosphodiesterase Inhibitors: Structure-Activity Relationships and Receptor Models (P. Erhardt). Abbreviations. Index.
J Beltman - One of the best experts on this subject based on the ideXlab platform.
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and Cellular Biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joseph A BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-nhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity. (Mol Cell Biochem 127/128: 239–253, 1993)
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and cellular biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joe BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-inhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity.
W K Sonnenburg - One of the best experts on this subject based on the ideXlab platform.
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and Cellular Biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joseph A BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-nhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity. (Mol Cell Biochem 127/128: 239–253, 1993)
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The role of protein phosphorylation in the regulation of cyclic nucleotide Phosphodiesterases.
Molecular and cellular biochemistry, 1993Co-Authors: J Beltman, W K Sonnenburg, Joe BeavoAbstract:The cyclic nucleotide Phosphodiesterases constitute a complex superfamily of enzymes responsible for catalyzing the hydrolysis of cyclic nucleotides. Regulation of cyclic nucleotide Phosphodiesterases is one of the two major mechanisms by which intracellular cyclic nucleotide levels are controlled. In many cases the fluctuations in cyclic nucleotide levels in response to hormones is due to the hormone responsiveness of the Phosphodiesterase. Isozymes of the cGMP-inhibited, cAMP-specific, calmodulin-stimulated and cGMP-binding Phosphodiesterases have been demonstrated to be substrates for protein kinases. Here we review the evidence that hormonally responsive phosphorylation acts to regulate cyclic nucleotide Phosphodiesterases. In particular, the cGMP-inhibited Phosphodiesterases, which can be phosphorylated by at least two different protein kinases, are activated as a result of phosphorylation. In contrast, phosphorylation of the calmodulin-stimulated Phosphodiesterases, which coincides with a decreased sensitivity to activation by calmodulin, results in decreased Phosphodiesterase activity.
Ilme Schlichting - One of the best experts on this subject based on the ideXlab platform.
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structure and mechanism of a bacterial light regulated cyclic nucleotide Phosphodiesterase
Nature, 2009Co-Authors: Thomas R. M. Barends, Elisabeth Hartmann, Mark Gomelsky, Dmitri A. Ryjenkov, Julia J. Griese, Thorsten Beitlich, Natalia V. Kirienko, Jochen Reinstein, Robert L. Shoeman, Ilme SchlichtingAbstract:BLUF is a photoreceptor protein domain that uses an FAD chromophore to sense blue light. Although X-ray crystal structures of single-domain BLUF proteins have been determined, there have not been any reports of a structure of a BLUF protein that also contained a functional 'output' domain. For this reason, the mechanism(s) of light activation for this class of photoreceptors has remained enigmatic. Here, Thomas Barends and colleagues report the first biochemical, structural, and mechanistic characterization of a full-length, active photoreceptor. The protein is from the bacterium Klebsiella pneumoniae, and it contains the BLUF sensor domain and a Phosphodiesterase output domain that hydrolyses cyclic dimeric GMP. The structures of this protein co-complexed with its substrate and metal ions provide a detailed understanding of how light absorbed by the BLUF domain leads to activation of the Phosphodiesterase output domain. Although structures of single-domain BLUF proteins—a photoreceptor protein domain that senses blue light—have been determined, there have been no reports of the structure of a BLUF protein containing a functional output domain; for this reason, the mechanism of light activation has remained enigmatic. The first biochemical, structural and mechanistic characterization of a full-length, active photoreceptor containing a BLUF sensor domain and a Phosphodiesterase EAL output domain is now reported. The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore1. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined2,3,4, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae5. BlrP1 consists of a BLUF sensor domain and a Phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria6,7,8,9. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP Phosphodiesterases. These structures also sketch out a path of light activation of the Phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain–domain interfaces.
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Structure and mechanism of a bacterial light-regulated cyclic nucleotide Phosphodiesterase.
Nature, 2009Co-Authors: Thomas R. M. Barends, Elisabeth Hartmann, Mark Gomelsky, Dmitri A. Ryjenkov, Julia J. Griese, Thorsten Beitlich, Natalia V. Kirienko, Jochen Reinstein, Robert L. Shoeman, Ilme SchlichtingAbstract:The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae. BlrP1 consists of a BLUF sensor domain and a Phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP Phosphodiesterases. These structures also sketch out a path of light activation of the Phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain-domain interfaces.
