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)

ZiPD (zinc phosphodiesterase; synonyms are ElaC, ecoZ, RNaseZ and 3' tRNase) and the iron-dependent redox enzyme FlRd (flavorubredoxin) from Escherichia coli represent prototypical cases of proteins sharing the metallo-beta-lactamase fold that require strict metal selectivity for catalytic activity, yet their metal selectivity has only been partially understood. In contrast with hydrolytic metallo-beta-lactamase proteins, iron-dependent FlRd-like enzymes have an atypical glutamate ligand, which replaces one otherwise conserved histidine ligand. X-ray absorption spectroscopy revealed that the FlRd metallo-beta-lactamase domain is capable of incorporating two zinc ions into the binuclear metal-binding site. Zinc dissociation constants, determined by isothermal titration calorimetry are similar for zinc binding to E. coli ZiPD (K(d1)=2.2+/-0.2 microM and K(d2)=23.0+/-0.6 microM) and to the E. coli FlRd metallo-beta-lactamase domain (K(d1)=0.7+/-0.1 microM and K(d2)=26.0+/-0.1 microM). In good correspondence, apo-ZiPD requires incubation with 10 microM zinc for full reconstitution of the phosphodiesterase activity. Accordingly, metal selectivity of ZiPD and FlRd only partially relies on first shell metal ligands. Back mutation of the atypical glutamate in FlRd to a histidine unexpectedly resulted in an increased first zinc dissociation constant (K(d1)=30+/-4 microM and K(d2)=23+/-2 microM). In combination with a recent mutational study on ZiPD [Vogel, Schilling and Meyer-Klaucke (2004) Biochemistry 43, 10379-10386], we conclude that the atypical glutamate does not guide metal selectivity of the FlRd metallo-beta-lactamase domain but suppresses possible hydrolytic cross-activity.
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PMID:Zinc- and iron-dependent cytosolic metallo-beta-lactamase domain proteins exhibit similar zinc-binding affinities, independent of an atypical glutamate at the metal-binding site. 1532 5

The heavy metal cadmium (Cd) is a human carcinogen that inhibits DNA repair activities. We show that DNA mismatch repair (MMR)-mediated cell cycle arrest after alkylation damage is suppressed by exposure to Cd and that this effect is reversed by preincubation with excess of zinc (Zn). We show that Cd-mediated inactivation of MMR activity is not caused by disruption of complex formation between the MMR proteins hEXO1-hMutS alpha and hEXO1-hMutL alpha nor does Cd inhibit 5'-exonuclease activity of hEXO1 in vitro. Thus, our studies show that exposure of human cells to Cd suppresses MMR activity, a repair activity known to play an important role in colon cancer and that this effect can be reversed by Zn treatment.
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PMID:Cadmium inhibits human DNA mismatch repair in vivo. 1535 9

Through the proteomic analysis using 2-dimensional electrophoresis, the nicotine addiction-associated proteins were extensively screened in the striatum of rat brains. The nicotine addiction was developed by repeated nicotine injection (0.4mg/kg s.c.), twice daily for 7 days, followed by one challenge injection after a 3 day withdrawal period, and then confirmed by observing a 2.3-fold increase in locomoter activity. The 3 up- and 4 down-regulated proteins were selected and identified to be zinc-finger binding protein-89 (ZBP-89), 2'3'-cyclic nucleotide 3'-phosphodiesterase 1, deoxyribonuclease 1-like 3 (DNase1l3), tandem pore domain halothane inhibited K(+) channel (THIK-2), brain-specific hyaluronan-binding protein (BRAL-1), death effector domain-containing DNA binding protein (DEDD), and brain-derived neurotrophic factor (BDNF) by mass spectrophotometric fingerprinting. Among them, the expression patterns of ZEB-89, DNase1l3, THIK-2, DEDD, and BDNF mRNAs were found to be coincident with those of cognate proteins, by using RT-PCR analysis. These proteins could be suggested as drug targets to develop a new therapy for nicotine-associated diseases, as well as the clues to understand the mechanism of nicotine.
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PMID:Proteomic analysis of nicotine-associated protein expression in the striatum of repeated nicotine-treated rats. 1558 80

Several extracellular DNases were detected after cultivation of Streptomyces aureofaciens B96 under submerged conditions. These DNases are nutritionally regulated and high content of amino acid nitrogen in cultivation medium repress their production. By varying cultivation conditions, there remained only two extracellular nuclease activities. The major one, extracellular endodeoxyribonuclease SaD I, was purified to homogeneity by ammonium sulfate precipitation, adsorption on Spheron, chromatography on Superose-12P followed by FPLC on MonoQ and final purification on HiTrapQ. The molecular weight of the purified SaD I determined by SDS-PAGE was 31 kDa. The DNase hydrolyses endonucleolytically both double-stranded and single-stranded circular and linear DNA. It does not cleave RNA and does not exhibit phosphodiesterase nor phosphomonoesterase activity. It requires a divalent cation (Zn2+, Co2+, Mn2+, Mg2+) and its activity optimum is at neutral pH (pH 7.2). The optimal temperature for DNA cleavage was 40 degrees C. Activity was strongly inhibited in the presence of phosphate, Hg2+, chelating agents or iodoacetate, but it was stimulated by addition of dimethyl sulphoxide.
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PMID:An extracellular endodeoxyribonuclease from Streptomyces aureofaciens. 1565 86

A phosphodiesterase model with two zinc centers has been synthesized and characterized. The compound, [Zn(2)(L(-)(2H))(AcO)(H(2)O)](PF(6)).2H(2)O (Zn(2)L'), was formed using an "end-off" type compartmental ligand, 2,6-bis{[(2-pyridylmethyl)(2-hydroxyethyl)amino]methyl}-4-methylphenol (L), and zinc acetate dihydrate. The X-ray crystallographic analysis shows that Zn(2)L' contains a mu-acetato-mu-cresolato-dizinc(II) core comprised of a quasi-trigonal bipyramidal Zn and a distorted octahedral Zn, and the distance between them is 3.421 Angstroms which is close to the dizinc distance in related natural metalloenzymes. Phosphodiesterase activity of Zn(2)L' was investigated using bis(4-nitrophenyl) phosphate (BNPP) as the substrate. The pH dependence of the BNPP cleavage in aqueous buffer media shows a sigmoid-shaped pH-k(obs) profile with an inflection point around pH 7.13 which is close to the first pK(a) value of 7.20 for Zn(2)L' obtained from the potentiometric titration. The catalytic rate constant (k(cat)) is 4.60 x 10(-6) s(-1) at pH 7.20 and 50 degrees C which is ca. 10(5)-fold higher than that of the uncatalyzed reaction. The deprotonated alcoholic group appended on Zn(2)L' is responsible for the cleavage reaction. The possible mechanism for the BNPP cleavage promoted by Zn(2)L' is proposed on the basis of kinetic and spectral analysis. The dizinc complex formed in situ in anhydrous DMSO exhibits a similar ability to cleave BNPP. This study provides a less common example for the phosphodiesterase model in which the metal-bound alkoxide is the nucleophile.
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PMID:An asymmetric dizinc phosphodiesterase model with phenolate and carboxylate bridges. 1587 22

Anandamide (N-arachidonoylethanolamine) is the first discovered endocannabinoid (endogenous ligand of cannabinoid receptors). In animal tissues, anandamide is principally formed together with other bioactive long-chain N-acylethanolamines from membrane glycerophospholipid by two enzyme reactions. The first reaction is the transfer of a fatty acyl chain from the sn-1 position of glycerophospholipid to phosphatidylethanolamine by calcium-dependent N-acyltransferase, resulting in the generation of N-acylphosphatidylethanolamine (NAPE). The second reaction is catalyzed by a phosphodiesterase of the phospholipase D (PLD)-type, which releases N-acylethanolamines from their corresponding NAPEs. The produced N-acylethanolamines are hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase or an amidase acting exclusively at acidic pH. Our recent cDNA cloning of the NAPE-hydrolyzing PLD (NAPE-PLD) from mouse, rat and human revealed that NAPE-PLD is a novel enzyme which has no homology with any known PLD enzymes, but belongs to the zinc metallo-hydrolase family of the beta-lactamase fold. The recombinant enzyme hydrolyzed various NAPEs, including the anandamide precursor N-arachidonoylphosphatidylethanolamine at similar rates, but was inactive with phosphatidylcholine and phosphatidylethanolamine. Considering cannabimimetic activities of anandamide, the enzymes involved in the biosynthesis and degradation of anandamide, including NAPE-PLD, may be promising targets for therapeutic agents.
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PMID:Endocannabinoid-related enzymes as drug targets with special reference to N-acylphosphatidylethanolamine-hydrolyzing phospholipase D. 1597 92

The newly recognized bacterial second messenger 3',5'-cyclic diguanylic acid (cyclic diguanylate (c-di-GMP)) has been shown to regulate a wide variety of bacterial behaviors and traits. Biosynthesis and degradation of c-di-GMP have been attributed to the GGDEF and EAL protein domains, respectively, based primarily on genetic evidence. Whereas the GGDEF domain was demonstrated to possess diguanylate cyclase activity in vitro, the EAL domain has not been tested directly for c-di-GMP phosphodiesterase activity. This study describes the analysis of c-di-GMP hydrolysis by an EAL domain protein in a purified system. The Vibrio cholerae EAL domain protein VieA has been shown to inversely regulate biofilm-specific genes (vps) and virulence genes (ctxA), presumably by decreasing the cellular pool of c-di-GMP. VieA was maximally active at neutral pH, physiological ionic strength, and ambient temperatures and demonstrated c-di-GMP hydrolytic activity with a Km of 0.06 microM. VieA was unable to hydrolyze cGMP. The putative metal coordination site of the EAL domain, Glu170, was demonstrated to be necessary for VieA activity. Furthermore, the divalent cations Mg2+ and Mn2+ were necessary for VieA activity; conversely, Ca2+ and Zn2+ were potent inhibitors of the VieA phosphodiesterase. Calcium inhibition of the VieA EAL domain provides a potential mechanism for regulation of c-di-GMP degradation.
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PMID:The EAL domain protein VieA is a cyclic diguanylate phosphodiesterase. 1608 14

The trace element zinc affects several aspects of immune function, such as the release of proinflammatory cytokines from monocytes. We investigated the role of cyclic nucleotide signaling in zinc inhibition of LPS-induced TNF-alpha and IL-1beta release from primary human monocytes and the monocytic cell line Mono Mac1. Zinc reversibly inhibited enzyme activity of phosphodiesterase-1 (PDE-1), PDE-3, and PDE-4 in cellular lysate. It additionally reduced mRNA expression of PDE-1C, PDE-4A, and PDE-4B in intact cells. Although these PDE can also hydrolyze cAMP, only the cellular level of cGMP was increased after incubation with zinc, whereas cAMP was found to be even slightly reduced due to inhibition of its synthesis. To investigate whether an increase in cGMP alone is sufficient to inhibit cytokine release, the cGMP analogues 8-bromo-cGMP and dibutyryl cGMP as well as the NO donor S-nitrosocysteine were used. All three treatments inhibited TNF-alpha and IL-1beta release after stimulation with LPS. Inhibition of soluble guanylate cyclase-mediated cGMP synthesis with LY83583 reversed the inhibitory effect of zinc on LPS-induced cytokine release. In conclusion, inhibition of PDE by zinc abrogates the LPS-induced release of TNF-alpha and IL-1beta by increasing intracellular cGMP levels.
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PMID:Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-alpha and IL-1 beta production in monocytes by elevation of guanosine 3',5'-cyclic monophosphate. 1617 17

Cyclic nucleotide phosphodiesterases constitute the only known mechanism to inactivate regulatory signals involving cAMP or cGMP. In our laboratory a cAMP-specific phosphodiesterase associated to the flagellar apparatus, named TcPDE1, was identified in Trypanosoma cruzi. By using the catalytic domain sequence of TcPDE1 to screen a Trypanosoma cruzi genomic data base, a novel T. cruzi phosphodiesterase sequence was found and characterized. TcPDE4 encodes a 924-amino acid protein and shows homology with the PDE4 vertebrate subfamily. The sequence shows three conserved domains, FYVE, phosphohydrolase and PDEaseI. The FYVE zinc-finger domain is characteristic of proteins recruited to phosphatidylinosytol 3-phosphate-containing membranes, whereas the two others are characteristic of phosphohydrolases and members of the cyclic nucleotide phosphodiesterases. Sequence analysis shows all characteristic domains present at the type-4 phosphodiesterases specific for cAMP. Moreover, TcPDE4 shows the inhibition profile characteristic for PDE4 subfamily, with an IC50 of 10.46 microM for rolipram and 1.3 microM for etazolate. TcPDE4 is able to complement a heat-shock-sensitive yeast mutant deficient in phosphodiesterase genes. The enzyme is specific for cAMP, Mg(2+)-dependent and its activity is not affected by cGMP or Ca(2+). The association of TcPDE4 with membranes was studied by subcellular fractionation of recombinant yeast and extraction in several conditions. Most of the enzyme remained associated to the membrane fraction after treatment with high salt concentration, detergent, or chaotropic agents. This support previous hypotheses that in this parasite cAMP phosphodiesterases, and consequently cAMP levels, are compartmentalized.
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PMID:TcPDE4, a novel membrane-associated cAMP-specific phosphodiesterase from Trypanosoma cruzi. 1622 37

Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [3H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+. The activity was abolished by site mutation of the predicted metal-binding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V(max) for PAF hydrolysis was 374 mumol x h(-1) x (mg of protein)(-1). The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.
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PMID:Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. 1625 17


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