Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Geometric and vibrational spectroscopic data (bond distances and angles, vibrational frequencies, infrared intensities) of pentachlorophenol-OH (PCP-OH) and pentachlorophenol-OD (PCP-OD) are calculated by density functional theory (B3LYP) using the 6-311G(d, p) basis set. Except for the vibrations involving the OH bond, the agreement between the experimental and calculated fundamental frequencies between 3600 and 400 cm-1 is very good. The theoretical method failed, however, to reproduce quantitatively the experimental intensities. The infrared spectra between 3600 and 10 000 cm-1 are studied, and the overtones or combination bands are assigned by comparing the spectra of PCP-OH and PCP-OD. The difference between the experimental and theoretical frequencies of the nu(OH) and nu(OD) frequencies can be mainly accounted for by the neglect of the anharmonicities of these vibrations in calculations. The binary or ternary combinations characterized by the highest coupling constants and the highest intensities are those involving the nu(OH), delta(OH), gamma(OH), and nu(C-O) vibrations. Copyright 1999 Academic Press.
J Mol Spectrosc 1999 Jun
PMID:Theoretical and Experimental (400-10 000 cm-1) Study of the Vibrational Spectrum of Pentachlorophenol. 1032 74

We describe the cloning and characterization of PCP, a novel calcium-binding protein that is expressed predominantly in the pistils and anthers of Brassica flowers late in flower development. A PCP cDNA - isolated from a subtracted cDNA library enriched in transcripts present in the pistil late in flower development - potentially encodes a 175 amino acid protein with a calculated molecular weight of 19.1 kDa. Other than limited homology to a repetitive C-terminal polyacidic region of PCP, none of the sequences in the GenBank database shares identity to PCP. This unique protein was purified from an Escherichia coli expression system and shown to bind calcium in a specific manner, both in a protein blot assay and by equilibrium dialysis. PCP binds 29 mol of calcium per mol of PCP protein with an apparent affinity constant of 3.2 x 10(2)/M, values consistent with the presence of a high capacity/low-affinity calcium-binding domain. PCP-specific mRNAs are detected predominantly in the stigma and style of pistils excised from open flowers; much lower levels of expression are seen in anthers of open flowers and in root and leaf tissue. Expression in the pistil steadily increases during flower development and peaks at flower opening. A PCP-specific antibody first detects the protein in pistils at one day prior to flowering, with higher levels of the protein seen in the pistils of open flowers. A low level of the protein is present in anthers of open flowers; however, PCP is not detected in either root or leaf extracts. The pattern of PCP expression is consistent with a possible role for PCP in pollen-pistil interactions or in pistil development. The results are also discussed in light of the central role calcium maintains in pollen tube growth and fertilization.
Plant Mol Biol 1999 Mar
PMID:A novel calcium-binding protein is expressed in Brassica pistils and anthers late in flower development. 1035 87

Phencyclidine (PCP) is a potent psychotomimetic drug of abuse and has profound effect on the functioning of the central nervous system (CNS). Many of the CNS functions are known to be mediated by calcium (Ca2+). In the present study we have investigated the effects of PCP on Ca2+ ATPase activity in rat brain both in vitro and in vivo. For in vitro studies, synaptic membrane fractions prepared from normal rat brain were incubated with PCP at different concentrations (25-100 microM) before the addition of substrate. For in vivo studies, rats were treated with a single moderate dose of PCP (10 mg/kg, i.p.) and animals were sacrificed at 1,2, 6 and 12 h after treatment. Ca2+ ATPase activity in synaptic membrane fractions was assayed by estimation of inorganic phosphate. PCP inhibited the Ca2+ ATPase in vitro in a concentration dependent manner with significant effect at 50 and 100 microM. A significant time-dependent reduction of the Ca2+ ATPase activity was evident in vivo. As early as 2 h after the treatment of rats with PCP the ATPase activity was significantly reduced. The reduction of Ca2+ ATPase observed even at 12 h after treatment suggesting a prolonged presence of the drug in the brain tissue. Further, kinetic studies in vitro indicated PCP to be a competitive inhibitor of Ca2+ ATPase with respect to the substrate, ATP. The present findings indicate that PCP inhibits synaptic membrane Ca2+ ATPase thus altering cellular Ca2+ homeostasis in CNS which may partially explain the pharmacological effects of the drug and/or its neurotoxicity.
Mol Cell Biochem 1999 Apr
PMID:Inhibition of calcium ATPase by phencyclidine in rat brain. 1039 Nov 37

1. Phencyclidine (PCP) is an inhibitor of the nicotinic acetylcholine receptor (AChR) with characteristics of an open-channel blocker. The location of PCP binding site on the AChR molecule is unknown. 2. PCP inhibits the AChR from electric organ with a higher potency than muscle AChR. To find the molecular basis of this difference, we expressed the two native and six hybrid receptors, and two receptors containing mutated mouse gamma subunits in Xenopus laevis oocytes. The inhibition of ACh-induced current in these receptors by PCP was studied using whole-cell voltage-clamp. All hybrid receptors generated robust ACh-induced currents, while incomplete receptors (gamma-less or delta-less) did not. 3. PCP potency was higher on hybrids containing Torpedo beta and gamma subunits regardless of the alpha and delta subunit origin. A mouse gamma subunit containing the asparagine 6' to the serine mutation in the M2 segment conferred a high sensitivity to PCP. 4. These results support the conclusion that the amino acid residues at the position 6' of the M2 segments contribute to the PCP potency difference between Torpedo and mouse receptors. 5. Another noncompetitive inhibitor of the AChR, the cembranoid eupalmerin acetate (EUAC), also inhibited the electric organ receptor with a somewhat higher potency than muscle AChR. However, the IC50 values for EUAC inhibition of hybrid receptors did not follow the pattern observed for PCP. Therefore, these two inhibitors interact differently with the AChR molecule.
Cell Mol Neurobiol 1999 Dec
PMID:Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ. 1045 35

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801, ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the posterior cingulate and retrosplenial cortex (PC/RSC). We have proposed that the neurotoxic action of these agents is mediated in part by a complex polysynaptic mechanism involving an interference in GABAergic inhibition resulting in excessive release of acetylcholine (ACh). Previously we have found that the systemic injection of GABAergic agents and alpha2-adrenergic agonists can block this neurotoxicity. In the present study we tested the hypothesis that NMDA antagonists trigger release of ACh in PC/RSC and that this action of NMDA antagonists is suppressed by GABAergic agents or alpha2-adrenergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (and the ability of pentobarbital, diazepam and clonidine to modify MK-801-induced ACh release) was studied in adult female rats using in vivo microdialysis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh output compared to basal levels. Pentobarbital, diazepam and clonidine suppressed MK-801's effect on ACh release. Exploratory studies indicated that the site of action of these agents was outside of the PC/RSC. The microdialysis results are consistent with several aspects of the circuitry proposed to mediate the neurotoxic action of NMDA antagonists.
Mol Psychiatry 1999 Jul
PMID:Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and alpha2-adrenergic agonists. 1048 51

Haloperidol augmented a trend of an increase in the heat shock protein (hsp70) mRNA levels induced by phencyclidine (PCP) in rat medial prefrontal cortex, nucleus accumbens and striatum, while the atypical antipsychotic drugs such as clozapine, olanzapine and risperidone decreased it. When administered alone, clozapine, but not haloperidol, decreased hsp70 mRNA levels. Haloperidol and the atypical antipsychotic drugs may thus have differential effects on hsp70 expression in some brain regions of PCP-treated rats.
Brain Res Mol Brain Res 1999 Nov 10
PMID:Effects of atypical antipsychotic drugs vs. haloperidol on expression of heat shock protein in the discrete brain regions of phencyclidine-treated rats. 1058 14

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gi phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.
J Mol Biol 2000 Feb 18
PMID:Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. 1066 8

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.
J Comput Aided Mol Des 2000 Feb
PMID:Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model. 1072 2

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gamma phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.
J Mol Biol 2000 May 19
PMID:Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. 1080 55

The properties of a ryanodine-sensitive Ca2+ release channel (receptor) in non-excitable cells like exocrine cells or epithelial cells are described in this review. The ryanodine-sensitive Ca2+ release from the microsomal vesicles is activated by Ca2+, caffeine, ryanodine or cyclic ADP-ribose (cADPR) and is inhibited by ruthenium red or higher concentrations (> or =100 microM) of ryanodine. The properties are similar to those of excitable cells such as muscle cells or neuronal tissues. In some non-excitable cells, the Ca2+ release induced by caffeine, ryanodine or cADPR is stimulated by calmodulin (CaM) or FK506. Kd values of [3H]ryanodine binding to the receptor protein range from 6 to 17 nM and are similar to those of a high-affinity binding site in skeletal or cardiac muscle. Maximum binding capacities (Bmax) range from 40 to 620 fmol/ mg protein and are 10 approximately 200-fold lower than those for a high-affinity binding site in skeletal muscle. Caffeine, adenine nucleotide AMP-PCP, Mg2+, ruthenium red or FK506 affects the binding. In some non-excitable cells, the ryanodine receptor (RyR) isoform RyR2 or RyR3 is expressed and has been identified. However, unlike for excitable cells, information concerning the RyR proteins, including binding sites for modulators like CaM and phosphorylation sites has not yet been obtained.
Int J Mol Med 2001 Jan
PMID:Ryanodine-sensitive Ca2+ release mechanism in non-excitable cells (Review). 1111 3


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