Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) is a primary inflammatory demyelinating disease of the human central nervous system, characterized by accumulation of mononuclear cells of hematogenous origin. RANTES is a C-C (beta)-chemokine family member with strong chemoattractant activity for lymphocytes and monocytes that are implicated in the pathogenesis of MS lesions. However, the cellular sources of RANTES message and the regulation of its secretion within diseased brain are poorly understood. Therefore, we carried out this study to compare the effect of Th1 cytokines on the induction of RANTES in different human astrocytic cell lines. IFN-gamma alone had little effect on RANTES production in both U-373MG and U-105MG cells, while TNF-alpha or IL-1beta alone had differential effects in the two cell lines. Low levels of RANTES chemokine were detected in culture supernatants from U-373MG cells. By contrast, TNF-alpha or IL-1beta dramatically increased RANTES secretion in U-105MG cells. Interestingly, different combination treatments of cells with the three cytokines synergistically induced RANTES release from both U-373MG and U-105MG cells. Consistent with these results, we found similar expression patterns for RANTES at the comparable steady-state mRNA levels in both cell lines. Furthermore, we showed that U-105MG cells treated with TNF-alpha and IL-1beta alone or in combination markedly induced increases in the rate of transcription of the RANTES chemokine gene. Our results indicate that these cell lines may be good model systems for studying the regulation of RANTES expression by cytokines in human glial cells.
Int J Mol Med 2001 Jul
PMID:Comparison of RANTES chemokine induction by Th1 cytokines in human astroglial cell lines. 1140 56

New bis[N-(2,6-di-t-butyl-1-hydroxyphenyl)salicylideneminato]copper(II) complexes bearing HO and CH3O substituents on the salicyaldehyde moiety were prepared, and their spectroscopic properties, as well as redox reactivity towards PbO2 and PPh3, examined by ESR and UV spectroscopy. In the process of synthesis of HO complexes unlike CH3O the oxidative C-C coupling of coordinated salicylaldimine ligands does not takes place. The powder ESR spectra of CH3O substituted complexes unlike of HO analogues are typical of a triplet state Cu(II) dimers with a half-field forbidden (deltaM = +/- 2) transition and the allowed transitions (AM = +/- 1) dimeric form of the complexes at 300 and 113 K. The one-electron oxidation of 3-CH3O and all of the OH complexes with PbO2 to give indophenoxyl type secondary radicals which are significantly different from those observed for analogues Cl, Br and NO2 substituted chelates. The presented complexes unlike their electron-withdrawing analogues are readily reduced by PPh3 via intramolecular electron transfer from ligand to copper(II) to give various radical intermediates as well as Cu(I) radical ligand compounds. The analysis of ESR spectra all of the complexes and radical intermediates are presented.
Spectrochim Acta A Mol Biomol Spectrosc 2001 Jul
PMID:Synthesis, spectroscopic characterization and ESR studies on electron transfer reactions of bis[N-(2,6-di-tert-butyl-1-hydroxyphenyl)salicylaldiminato]-copper(II) complexes with PbO2 and PPh3. 1147 18

The calculation of side chain centers of coordinates and the subsequent generation of side chain-side chain and side chain-backbone distance matrices is suggested as an improved method for viewing interactions inside proteins and for the comparison of protein structures. The use of side chain distance matrices is demonstrated with free PTI, and the use of difference distance matrices for side chains is shown for free and trypsin-bound PTI as well as for the X-ray structures of trypsin complexes with PTI and with benzamidine. It is found that conformational variations are reflected in the side chain distance matrices much more than in the standard C-C distance representations.
J Mol Struct 1986
PMID:An improved approach to the analysis of drug-protein binding by distance geometry. 1154 40

The natural templates (NT) superimposition method is used to determine the pharmacophoric requirements of the A subtype of the gamma-aminobutyric acid (GABA) receptor. Bioactive conformations for antagonists and agonists are found by superimposing them on a relatively rigid alkaloid bicuculline, which itself is a competitive antagonist at this ligand-gated ion channel receptor. As has been usual in the application of this modeling method, consideration of available experimental data is the cornerstone for obtaining realistic models. The identification of two substructural fragments of bicuculline permitted classification of the ligands. Analysis of the antagonists and agonists with respect to the two substructural fragments revealed two bioactive conformations of the highly flexible GABA molecule, one of which is extended with the nonhydrogenic atoms roughly coplanar torsional angles of -37 and -179 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively. The second bioactive compound is clearly non planar (torsional angles of -81 and -109 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively).
J Mol Graph Model 2001
PMID:Superimposition-based protocol as a tool for determining bioactive conformations. II. Application to the GABA(A) receptor. 1177 4

Mimosine is a non-toxic plant aminoacid which is an effective inhibitor of DNA replication by acting at the S-phase. In this study we infected mice with T. spiralis, a nematode parasite, and studied the inflammatory response through the determination of MIP-2, a C-X-C chemokine and MCP-1, a C-C chemokine in the inflamed area around the parasitic cyst. The animals were infected and their diaphragms were tested for inflammatory response. MCP-1 and MIP-2 was tested after 1, 10, 20, 30, and 40 days post inoculation, before and after mimosine treatment. The inflammatory index was calculated by counting the white blood cells around the nematode cysts, while expression of MIP-2 and MCP-1 was calculated by ELISA method and transcription by Northern blot and RT-PCR. Here we found that mimosine strongly inhibited the inflammatory index in the diaphragmatic tissue at 10, 20, 30 and 40 days post-treatment. In these experiments, mimosine had no effect on the number of cysts produced. In addition, we found that MCP-1 transcription and translation was completely inhibited by mimosine, while MIP-2 transcription and translation was partially inhibited at 30 and 40 days; yet it was totally inhibited after 10 and 20 days in encysted diaphragm tissue infected by T. spiralis. Our studies suggest that mimosine has an inhibitory effect through the inhibition of cytoplasmatic serine hydroxymethyltransferase altering the cell cycle of white blood cells. This study suggests for the first time the premise that mimosine acts as an anti-inflammatory compound.
Mol Cell Biochem 2002 Jan
PMID:Inhibition of MCP-1 and MIP-2 transcription and translation by mimosine in muscle tissue infected with the parasite Trichinella spiralis. 1193 38

All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen (PBG) as a common precursor. Porphobilinogen synthase (PBGS) synthesizes PBG through the asymmetric condensation of two molecules of aminolevulinic acid (ALA). Crystal structures of PBGS from various sources confirm the presence of two distinct binding sites for each ALA molecule, termed A and P. We have solved the structure of the active-site variant D139N of the Mg2+-dependent PBGS from Pseudomonas aeruginosa in complex with the inhibitor 5-fluorolevulinic acid at high resolution. Uniquely, full occupancy of both substrate binding sites each by a single substrate-like molecule was observed. Both inhibitor molecules are covalently bound to two conserved, active-site lysine residues, Lys205 and Lys260, through Schiff bases. The active site now also contains a monovalent cation that may critically enhance enzymatic activity. Based on these structural data, we postulate a catalytic mechanism for P. aeruginosa PBGS initiated by a C-C bond formation between A and P-side ALA, followed by the formation of the intersubstrate Schiff base yielding the product PBG.
J Mol Biol 2002 Jul 05
PMID:Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism. 1207 82

The mechanism of orotidine 5-monophosphate decarboxylase (ODCase) has been modeled using hybrid Density Functional Theory (B3LYP functional). The main goal of the present study was to investigate if much larger quantum chemical models of the active site than previously used could shed new light on the mechanism. The models used include the five conserved amino acids expected to be the most important ones for catalysis. One result of this model is that a mechanism involving a direct cleavage of the C-C bond followed by a protonation of C6 by Lys93 appears unlikely, with a barrier for decarboxylation 20 kcal mol(-1) too high. Additional effects like electrostatic stress and ground-state destabilization have been estimated to have only a minor influence on the reaction barrier. The conclusion from the calculations is that the negative charge developing on the substrate during decarboxylation must be stabilized by a protonation of the carbonyl O2 of the substrate. For this mechanism, the addition of the catalytic amino acids decreases the reaction barrier by 25 kcal mol(-1), but full agreement with experimental results has still not been reached. Further modifications of this mechanism are discussed.
J Mol Model 2002 Apr
PMID:Density functional models of the mechanism for decarboxylation in orotidine decarboxylase. 1211 91

The structures and spectra of mono and dianionic species derived from PhCH2CN under the action of an organic base LHMDS or n-BuLi in THF solution have been investigated by vibrational spectroscopy and DFT calculations. The assignments previously proposed for the monoanion, the bridged, linear and dimeric monoanionic ion pairs compare well with the calculated ones. The addition of HMPA to a THF solution of PhCHCNLi leads to the formation of an HMPA solvated linear ion pair, distinguishable from the bridged ion pair by the wave number of the 8a v(CC) phenyl ring mode. The calculated structure of the phenylacetonitrile anion in the (PhCHCNLi, CH3Li) mixed dimer or 'Quadac' is very similar to that in the linear ion pair or in the dimer and to that observed by X-ray in (PhCHCNLi, [CH(CH9)2]2NLi) 'Quadac'. The structure of the anion is planar, indicating a charge delocalization from the benzene ring to the -CHCN group. The calculated spectra of the free, mono and dilithiated dianionic species compare well with the experimental ones of the species formed under addition of more than one equivalent of n-BuLi. The structure of the >C-C-CN2- group is very close to that of an imine. The v(CN) bands of the free, mono and dilithiated dianionic species are located at 1912, 1930 and 1890 cm(-1), respectively. The large wave number shift observed between the free monoanion and dianion (approximately 176 cm(-1)), in good accordance with the calculated one (170 cm(-1)) allows differentiating mono and dianionic species. The shifts observed for the 8a and 19a v(CC) phenyl ring modes, although much smaller, also allows discriminating the different species. These small shifts indicate a small variation of the electronic delocalization in the benzene ring in agreement with the calculations.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Jul
PMID:Structural and vibrational characterization of the mono and dilithiated species derived from phenylacetonitrile in THF by infrared and Raman spectroscopy and density functional theory calculations. 1216 96

Vibrational characteristics of CD3CN solutions of LiClO4 and NaClO4 have been studied by means of infrared and Raman spectroscopy. Blue shifts of 22 and 11 cm(-1) of the v2 C[triple bond]N stretch are observed resulting from interaction of CD3CN with Li+ and Na+, respectively. The number of primary solvation sites of both Li+ and Na+ in acetonitrile is believed to be four from the comparison of the Raman intensities of the C[triple bond]N stretch for free CD3CN and those coordinated to Li+ and Na+. Evidently formation of contact ion pairs of the cation (Li+ or Na+) and anion (ClO4-) is more probable at a higher concentration of the salt. The characteristics of the v2 C[triple bond]N stretch, v4 C-C stretch, and v8 CCN deformation bands vary substantially upon coordination, while other vibrational bands are relatively immune to the donor-acceptor interaction. DFT calculations have also been performed at the BLYP/6-31 + G(2d,p) level to examine the structures and vibrational characteristics of CD3CN coordinated to Li+ and Na+. The calculated results are in good agreement with the observed vibrational characteristics.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Jun
PMID:Solvation of LiClO4 and NaClO4 in deuterated acetonitrile studied by means of infrared and Raman spectroscopy. 1216 45

We have previously reported that the fragility of skin, tendon and bone from the oim mouse is related to a significant reduction in the intermolecular cross-linking. The oim mutation is unlikely to affect the efficacy of the lysyl oxidase, suggesting that the defect is in the molecule and fibre. We have therefore investigated the integrity of both the oim collagen molecules and the fibre by differential scanning calorimetry. The denaturation temperature of the oim molecule in solution and the fibre from tail tendon were found to be higher than the wild-type by 2.6deg.C and 1.9deg.C, respectively. With the loss of the alpha2 chain, the hydroxyproline content of the homotrimer is higher than the heterotrimer, which may account for the increase. There is a small decrease in the enthalpy of the oim fibres but it is not significant, suggesting that the amount of disorder of the triple-helical molecules and of the fibres is small and involves only a small part of the total bond energy holding the helical structure together. The difference in denaturation temperature of the skin collagen molecules (t(m)) and fibres (t(d)) is significantly lower for the oim tissues, 19.9deg.C against 23.1deg.C, indicating reduced molecular interactions and hence packing of the molecules in the fibre. Computation of the volume fraction of the water revealed that the interaxial separation of the oim fibres was indeed greater, increasing from 19.6A to 21.0A. This difference of 1.4A, equivalent to a C-C bond, would certainly decrease the ability of the telopeptide aldehyde to interact with the epsilon -amino group from an adjacent molecule and form a cross-link. We suggest, therefore, that the reduction of the cross-linking is due to increased water content of the fibre rather than a distortion of the molecular structure. The higher hydrophobicity of the alpha2 chain appears to play a role in the stabilisation of heterotrimeric type I collagen, possibly by increasing the hydrophobic interactions between the heterotrimeric molecules, thereby reducing the water content and increasing the binding of the molecules in the fibre.
J Mol Biol 2002 Aug 30
PMID:The role of the alpha2 chain in the stabilization of the collagen type I heterotrimer: a study of the type I homotrimer in oim mouse tissues. 1220 62


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