Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The X-ray crystal structure of the Escherichia coli (Ec) direct oxygen sensor heme domain (Ec DosH) has been solved to 1.8 A using Fe multiple-wavelength anomalous dispersion (MAD), and the positions of Met95 have been confirmed by selenomethionine ((Se)Met) MAD. Ec DosH is the sensing part of a larger two-domain sensing/signaling protein, in which the signaling domain has phosphodiesterase activity. The asymmetric unit of the crystal lattice contains a dimer comprised of two differently ligated heme domain monomers. Except for the heme ligands, the monomer heme domains are identical. In one monomer, the heme is ligated by molecular oxygen (O(2)), while in the other monomer, an endogenous Met95 with S --> Fe ligation replaces the exogenous O(2) ligand. In both heme domains, the proximal ligand is His77. Analysis of these structures reveals sizable ligand-dependent conformational changes in the protein chain localized in the FG turn, the G(beta)-strand, and the HI turn. These changes provide insight to the mechanism of signal propagation within the heme domain following initiation due to O(2) dissociation.
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PMID:Insights into signal transduction involving PAS domain oxygen-sensing heme proteins from the X-ray crystal structure of Escherichia coli Dos heme domain (Ec DosH). 1500 9

CR3465 (L-Tyrosine, N-[(2-quinolinyl)carbonyl]-O-(7-fluoro-2-quinolinylmethyl) sodium salt) is a potent antagonist of [3H]leukotriene D4 ([3H]LTD4) binding to guinea pig lung preparations, its Ki (4.7+/-0.7 nM) being comparable with that of montelukast (5.6+/-0.6 nM). In tracheal strips from standard or ovalbumin-sensitized guinea pigs, CR3465 caused parallel rightward shifts in the concentration-response curves obtained with either LTD4 or antigen (pA(2), 8.74 and 8.15). Intravenous (i.v.) administration of the agent both antagonized (ED50, 9.9+/-1.9 microg/kg) and reverted LTD4 -induced bronchoconstriction of anesthetized guinea pigs. CR3465 reduced inflammatory infiltrates in the bronchoalveolar lavage fluid after antigen challenge of sensitized animals, and proved also active in inhibiting phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) activities exhibited by human platelets and neutrophils (IC50, 2.01+/-0.07 and 4.7+/-0.5 microM). In line with properties shown by phosphodiesterase inhibitors, CR3465 reduced the contractile response of guinea pig airways to histamine and decreased N-formyl-Met-Leu-Phe (fMLP)-induced degranulation of human neutrophils (IC50, 13.8 microM). Oral administration (20 mg/kg) of the compound in rats produced a significant (37%) ex vivo inhibition of tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide-stimulated whole blood. Pharmacokinetic data in the rat demonstrated approximately 100% bioavailability of the agent. We conclude that CR3465 represents a potent leukotriene CysLT1 receptor antagonist with enhanced effects, being also useful for counteracting spasmogenic and inflammatory stimuli other than those elicited by cysteinyl-leukotrienes (Cys-LTs).
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PMID:Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity. 1554 26

Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy.
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PMID:Preferential inhibition of human phosphodiesterase 4 by ibudilast. 1631 25

Paired Y-organs secrete ecdysteroid hormones that control cycles of growth and molting in crustaceans. Y-Organs are regulated, at least in part, by molt-inhibiting hormone (MIH), a polypeptide produced and released by the X-organ/sinus gland complex of the eyestalks. In the present studies, crab (Callinectes sapidus) Y-organs were incubated in vitro in the presence of [(35)S]methionine, and cyclic nucleotide analogs or experimental agents that influence the cAMP signaling pathway. In 4-hr incubations, 8-Br-cAMP and db-cAMP (but not 8-Br-cGMP) suppressed incorporation of [(35)S]methionine into Y-organ proteins; the effect of 8-Br-cAMP was concentration-dependent. Autoradiograms of radiolabeled Y-organ proteins separated on SDS-PAGE gels indicated the effect of 8-Br-cAMP was general (as opposed to selective) suppression of protein synthesis. Addition of both forskolin (an adenylyl cyclase activator) and 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) likewise suppressed incorporation of [(35)S]methionine into Y-organ proteins. Cycloheximide (a protein synthesis inhibitor) suppressed incorporation of [(35)S]methionine into Y-organ proteins and secretion of ecdysteroids. The combined results suggest that cAMP is involved in regulation of protein synthesis in C. sapidus Y-organs. We are currently investigating the link of protein synthesis to ecdysteroid production, and the possibility of cross-talk between cAMP and other cellular signaling pathways in Y-organs.
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PMID:Regulation of protein synthesis in Y-organs of the blue crab (Callinectes sapidus): involvement of cyclic AMP. 1649 43

In earlier studies from this laboratory, Xanthomonas campestris pv. glycines was found to exhibit a nutrition stress-related postexponential rapid cell death (RCD). The RCD was exhibited in protein-rich media but not in starch or other minimal media. This RCD in X. campestris pv. glycines was found to display features similar to those of the programmed cell death (PCD) of eukaryotes. Results of the present study showed that the observed RCD in this organism is both positively and negatively regulated by small molecules. The amino acids glycine and l-alanine as well as the D isomers of valine, methionine, and threonine were found to induce the synthesis of an active caspase-3-like protein that was associated with the onset of RCD. Addition of pyruvate and citrate to the culture medium induced both the synthesis of active caspase-3-like protein and RCD. Higher levels of intracellular accumulation of pyruvate and citrate were also observed under conditions favoring RCD. On the other hand, dextrin and maltose, the hydrolytic products of starch, inhibited the synthesis of the caspase-3-like protein. Addition of glucose and cyclic AMP (cAMP) to the RCD-favoring medium prevented RCD. Glucose, cAMP, caffeine (a known inhibitor of a phosphodiesterase that breaks down cAMP), and forskolin (from the herb Coleus forskholii, known to activate the enzyme adenylate cyclase that forms cAMP) inhibited the caspase enzyme activity in vivo and consequently the RCD process. The addition of glucose and other inhibitors of RCD enhanced intracellular cAMP accumulation. This is the first report demonstrating the involvement of small molecules in the regulation of nutrition stress-related stationary-phase rapid cell death in X. campestris pv. glycines, which is programmed.
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PMID:Molecules involved in the modulation of rapid cell death in Xanthomonas. 1685 30

Heme-regulated phosphodiesterase from Escherichia coli (Ec DOS) is a gas-sensor enzyme that hydrolyzes cyclic dinucleotide-GMP, and it is activated by O(2) or CO binding to the Fe(II) heme. In contrast to other well known heme-regulated gas-sensor enzymes or proteins, Ec DOS is not specific for a single gas ligand. Because Arg(97) in the heme distal side in Ec DOS interacts with the O(2) molecule and Met(95) serves as the axial ligand on the distal side of the Fe(II) heme-bound PAS domain of Ec DOS, we explored the effect of mutating these residues on the activity and gas specificity of Ec DOS. We found that R97A, R97I, and R97E mutations do not significantly affect regulation of the phosphodiesterase activities of the Fe(II)-CO and Fe(II)-NO complexes. The phosphodiesterase activities of the Fe(II)-O(2) complexes of the mutants could not be detected due to rapid autoxidation and/or low affinity for O(2). In contrast, the activities even of the gas-free M95A and M95L mutants were similar to that of the gas-activated wild-type enzyme. Interestingly, the activity of the M95H mutant was partially activated by O(2), CO, and NO. Spectroscopic analysis indicated that the Fe(II) heme is in the 5-coordinated high-spin state in the M95A and M95L mutants but that in the M95H mutant, like wild-type Ec DOS, it is in the 6-coordinated low-spin state. These results suggest that Met(95) coordination to the Fe(II) heme is critical for locking the system and that global structural changes around Met(95) caused by the binding of the external ligands or mutations at Met(95) releases the catalytic lock and activates catalysis.
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PMID:Critical role of the heme axial ligand, Met95, in locking catalysis of the phosphodiesterase from Escherichia coli (Ec DOS) toward Cyclic diGMP. 1753 5

The phosphodiesterase-11A (PDE11) family consists of four splice variants (PDE11A1-PDE11A4) that contain a conserved carboxyl-terminal (C-terminal) catalytic domain that hydrolyzes cAMP and cGMP; the amino-termini (N-termini) vary in length and amino acid sequence. PDE11A2, PDE11A3, and PDE11A4 contain one or more GAF (cGMP-binding phosphodiesterase, Anabaena adenylyl cyclase, and Escherichia coli FhlA) subdomains. In the present study, PDE11A1 and PDE11A2 demonstrated higher affinity for cAMP and cGMP when directly compared to that of the longest isoform, PDE11A4. Moreover, PDE11A3, PDE11A2, and PDE11A1, which contain progressively shorter N-termini, were more sensitive than PDE11A4 to inhibition by two structurally unrelated inhibitors, tadalafil (Cialis) and vardenafil (Levitra). The substrate and inhibitor affinity differences among the PDE11 isozymes could not be ascribed to differences in their quaternary structure since PDE11A4, PDE11A3, and PDE11A2 were determined to be dimers, and PDE11A1 was a tetramer. These data also demonstrate that PDE11 isozymes containing at least 123 C-terminal amino acids of the GAF-B domain are stable oligomers and that GAF-A is not required for oligomerization. The isolated PDE11 catalytic domain (Met-563-Asn-934) displayed both monomeric and dimeric forms, and upon dilution, this domain was primarily monomeric, indicating that the main oligomerization contacts are within the N-termini of PDE isozymes. This report is the first to describe an inhibitory effect of the N-terminal region of PDE11A4 on the affinity of the catalytic domain for both substrates and inhibitors and the first to define the quaternary structure and the regions that contribute to this structure within the human PDE11A family.
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PMID:N-Terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. 1769 99

The direct oxygen sensor protein isolated from Escherichia coli (Ec DOS) is a heme-based signal transducer protein responsible for phosphodiesterase (PDE) activity. Binding of O(2), CO, or NO to a reduced heme significantly enhances the PDE activity toward 3',5'-cyclic diguanylic acid. We report stationary and time-resolved resonance Raman spectra of the wild-type and several mutants (Glu-93 --> Ile, Met-95 --> Ala, Arg-97 --> Ile, Arg-97 --> Ala, Arg-97 --> Glu, Phe-113 --> Leu, and Phe-113 --> Thr) of the heme-containing PAS domain of Ec DOS. For the CO- and NO-bound forms, both the hydrogen-bonded and non-hydrogen-bonded conformations were found, and in the former Arg-97 forms a hydrogen bond with the heme-bound external ligand. The resonance Raman results revealed significant interactions of Arg-97 and Phe-113 with a ligand bound to the sixth coordination site of the heme and profound structural changes in the heme propionates upon dissociation of CO. Mutation of Phe-113 perturbed the PDE activities, and the mutation of Arg-97 and Phe-113 significantly influenced the transient binding of Met-95 to the heme upon photodissociation of CO. This suggests that the electrostatic interaction of Arg-97 and steric interaction of Phe-113 are crucial for regulating the competitive recombination of Met-95 and CO to the heme. On the basis of these results, we propose a model for the role of the heme propionates in communicating the heme structural changes to the protein moiety.
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PMID:Roles of Arg-97 and Phe-113 in regulation of distal ligand binding to heme in the sensor domain of Ec DOS protein. Resonance Raman and mutation study. 1845 Jul 54

Dos from Escherichia coli is a bacterial gas sensor protein comprising a heme-containing gas sensor domain and a phosphodiesterase catalytic domain. Using a combination of static light scattering and gel filtration experiments, we established that, as are many other sensor proteins, the full-length protein is dimeric. The full-length dimer (association constant <10 nm) is more stable than the dimeric heme domain (association constant approximately 1 mum), and the dimer interface presumably includes both sensor and catalytic domains. Ultrafast spectroscopic studies showed little influence of the catalytic domain on kinetic processes in the direct vicinity of the heme. By contrast, the properties of ligand (CO and O(2)) binding to the heme in the sensor domain, occurring on a microsecond to second time scale, were found to be influenced by (i) the presence of the catalytic domain, (ii) the dimerization state, and in dimers, (iii) the ligation state of the other subunit. These results imply allosteric interactions within dimers. Steady-state titrations demonstrated marked cooperativity in oxygen binding to both the full-length protein and the isolated heme domain, a feature not reported to date for any dimeric sensor protein. Analysis of a variety of time-resolved experiments showed that Met-95 plays a major role in the intradimer interactions. The intrinsic binding and dissociation rates of Met-95 to the heme were modulated approximately 10-fold by intradimer and sensor-catalytic domain interactions. Dimerization effects were also observed for cyanide binding to the ferric heme domains, suggesting a similar role for Met-95 in ferric proteins.
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PMID:Heme ligand binding properties and intradimer interactions in the full-length sensor protein dos from Escherichia coli and its isolated heme domain. 1986 14

The pericarp of Sapindus mukorossi Gaertn is traditionally used as an expectorant in Japan, China, and Taiwan. Activated neutrophils produce high concentrations of the superoxide anion (O(2)(-)) and elastase known to be involved in airway mucus hypersecretion. In the present study, the anti-inflammatory functions of hederagenin 3-O-(3,4-O-di-acetyl-alpha-L-arabinopyranoside)-(1-->3)-alpha-l-rhamnopyranosyl-(1-->2)-alpha-l-arabinopyranoside (SMG-1), a saponin isolated from S. mukorossi, and its underlying mechanisms were investigated in human neutrophils. SMG-1 potently and concentration-dependently inhibited O(2)(*-) generation and elastase release in N-Formyl-Met-Leu-Phe (FMLP)-activated human neutrophils. Furthermore, SMG-1 reduced membrane-associated p47(phox) expression in FMLP-induced intact neutrophils, but did not alter subcellular NADPH oxidase activity in reconstituted systems. SMG-1 attenuated FMLP-induced increase of cytosolic calcium concentration and phosphorylation of p38 MAPK, ERK, JNK, and AKT. However, SMG-1 displayed no effect on cellular cAMP levels and activity of adenylate cyclase and phosphodiesterase. Significantly, receptor-binding analysis showed that SMG-1 inhibited FMLP binding to its receptor in a concentration-dependent manner. In contrast, neither phorbol myristate acetate-induced O(2)(*-) generation and MAPKs activation nor thapsigargin-caused calcium mobilization was altered by SMG-1. Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases.
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PMID:The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation. 2059 99


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