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At least 775 records · Page 43Linked to original sources
PubMed2005

Two competitive routes in the lactim-lactam phototautomerization of a hydroxypyridine derivative cation in water: dissociative mechanism versus water-assisted proton transfer.

Ground-state tautomerism and excited-state proton-transfer processes of 2-(6'-hydroxy-2'-pyridyl)benzimidazolium in H2O and D2O have been studied by means of UV-vis absorption and fluorescence spectroscopy in both steady-state and time-resolved modes. In the ground state, this compound shows a tautomeric equilibrium between the lactim cation, protonated at the benzimidazole N3, and its lactam tautomer, obtained by proton translocation from the hydroxyl group to the pyridine nitrogen. Direct excitation of the lactam tautomer leads to its own fluorescence emission, while as a result of the increase of acidity of the OH group and basicity at the pyridine N upon excitation, the lactim species undergoes a proton translocation from the hydroxyl group to the nitrogen, favoring the lactam structure in the excited state. No fluorescence emission from the initially excited lactim species was detected due to the ultrafast rate of the excited-state proton-transfer processes. The lactim-lactam phototaumerization process takes place via two competitive excited-state proton-transfer routes: a one-step water-assisted proton translocation (probably a double proton transfer) and a two-step pathway which involves first the dissociation of the lactim cation to form an emissive intermediate zwitterionic species and then the acid-catalyzed protonation at the pyridine nitrogen to give rise to the lactam tautomer.

Cations↗
PubMed2000

Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors.

This review examines the evidence for the development of adverse effects due to prolonged gastric acid suppression with proton pump inhibitors. Potential areas of concern regarding long-term proton pump inhibitor use have included: carcinoid formation; development of gastric adenocarcinoma (especially in patients with Helicobacter pylori infection); bacterial overgrowth; enteric infections; and malabsorption of fat, minerals, and vitamins. Prolonged proton pump inhibitor use may lead to enterochromaffin-like cell hyperplasia, but has not been demonstrated to increase the risk of carcinoid formation. Long-term proton pump inhibitor treatment has not been documented to hasten the development or the progression of atrophic gastritis to intestinal metaplasia and gastric cancer, although long-term studies are required to allow definitive conclusions. At present, we do not recommend that patients be tested routinely for H. pylori infection when using proton pump inhibitors for prolonged periods. Gastric bacterial overgrowth does increase with acid suppression, but important clinical sequelae, such a higher rate of gastric adenocarcinoma, have not been seen. The risk of enteric infection may increase with acid suppression, although this does not seem to be a common clinical problem with prolonged proton pump inhibitor use. The absorption of fats and minerals does not appear to be significantly impaired with chronic acid suppression. However, vitamin B12 concentration may be decreased when gastric acid is markedly suppressed for prolonged periods (e.g. Zolllinger-Ellison syndrome), and vitamin B12 levels should probably be assessed in patients taking high-dose proton pump inhibitors for many years. Thus, current evidence suggests that prolonged gastric acid suppression with proton pump inhibitors rarely, if ever, produces adverse events. Nevertheless, continued follow-up of patients taking proton pump inhibitors for extended periods will provide greater experience regarding the potential gastrointestinal adverse effects of long-term acid suppression.

Adenocarcinoma↗
PubMed2002

Single vs. double dose of a proton pump inhibitor in triple therapy for Helicobacter pylori eradication: a meta-analysis.

BACKGROUND: Triple therapies combining a double dose of proton pump inhibitor plus two antibiotics are the standard treatment for Helicobacter pylori infection. Some reports suggest that the use of half the dose of proton pump inhibitor is equally effective. AIM: To compare the efficacy of a single vs. double dose of proton pump inhibitor in triple therapy. METHODS: We conducted a MEDLINE search. The search strategy included the words (pylori) AND (triple, PPI, proton pump, omeprazole, rabeprazole, pantoprazole, lansoprazole, clarithromycin, amoxicillin, amoxycillin or metronidazole). Abstracts of the articles obtained and papers presented at the European Helicobacter pylori Study Group and American Gastroenterological Association congresses from 1996 to 2001 were examined. Inclusion criteria were: (i) randomized studies with at least two branches of triple therapy including a proton pump inhibitor and two standard antibiotics; (ii) branches could differ only in terms of proton pump inhibitor dosage. A meta-analysis was conducted using conventional shareware (Review Manager 4.1). RESULTS: Thirteen studies met the inclusion criteria with a total of 2391 patients. Cure rates with double doses of proton pump inhibitor were higher in both the intention-to-treat analysis (83.9% vs. 77.7%; Peto odds ratio, 1.51; 95% confidence interval, 1.23-1.85; P < 0.01) and per protocol analysis (89% vs. 81%; Peto odds ratio, 1.96; 95% confidence interval, 1.55-2.47; P < 0.01). CONCLUSION: Triple therapies containing a single dose of proton pump inhibitor are less effective than those containing a standard double dose of proton pump inhibitor.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

A substrate-induced change in the stereospecificity of the serine-hydroxymethyltransferase-catalysed exchange of the alpha-protons of amino acids--evidence for a second catalytic site.

NMR has been used to study the catalysis of the hydrogen-deuterium exchange of the alpha-protons of amino acids by serine hydroxymethyltransferase (EC 2.1.2.1) from Escherichia coli. 13C-NMR was used to follow the exchange of the alpha-protons of [2-13C]glycine. The enzyme-catalysed first-order exchange rate of the pro-2S proton of glycine was approximately 7000 times more efficient than that of the pro-2R proton of glycine at both pH 7.0 and 7.8. 1H-NMR was used to follow the hydrogen-deuterium exchange rates of the alpha-protons of L- and D-2-amino derivatives of butyric, pentanoic and hexanoic acids at pH 7.8. Increasing the size of the R-group leads to a progressive change in the stereospecificity of the exchange reaction from the pro-2S proton of glycine to the 2R proton of L-amino acids. The stereospecificity for the alpha-protons of L-amino acids increased as the size of the R-group increased. With glycine, removal of tetrahydrofolate led to a large decrease in the stereospecificity of the exchange reaction but did not affect the exchange rates of the alpha-protons of any of the larger amino acids studied. We show that the Schiff base formed between L-2-aminohexanoic acid (L-norleucine) and pyridoxal 5'-phosphate binds at a different site from the Schiff base between glycine and pyridoxal 5'-phosphate. The molecular basis of these results is discussed.

Amino Acids↗
PubMed2005

Computer simulation of explicit proton translocation in cytochrome c oxidase: the D-pathway.

Proton translocation in the D-pathway of cytochrome c oxidase has been studied by a combination of classical molecular dynamics and the multistate empirical valence bond methodology. This approach allows for explicit Grotthuss proton hopping between water molecules. According to mutagenesis experiments, the role of proton donor/acceptor along the D-pathway is carried by the highly conserved residue Glu-242. The present multistate empirical valence bond simulations indicate that the protonation/deprotonation state of Glu-242 is strongly coupled to the distance of proton propagation in the D-pathway. The proton was seen to travel the full length of the D-pathway when Glu-242 was deprotonated; however, it was trapped halfway along the path when Glu-242 was protonated. Further investigation in terms of both proton dynamical properties and free energy calculations for the pathway of proton transport provides evidence for a two-step proton transport mechanism in the D-pathway.

Animals↗
PubMed2003

The low-spin heme of cytochrome c oxidase as the driving element of the proton-pumping process.

Mitochondrial cytochrome c oxidase plays an essential role in aerobic cellular respiration, reducing dioxygen to water in a process coupled with the pumping of protons across the mitochondrial inner membrane. An aspartate residue, Asp-51, located near the enzyme surface, undergoes a redox-coupled x-ray structural change, which is suggestive of a role for this residue in redox-driven proton pumping. However, functional or mechanistic evidence for the involvement of this residue in proton pumping has not yet been obtained. We report that the Asp-51 --> Asn mutation of the bovine enzyme abolishes its proton-pumping function without impairment of the dioxygen reduction activity. Improved x-ray structures (at 1.8/1.9-A resolution in the fully oxidized/reduced states) show that the net positive charge created upon oxidation of the low-spin heme of the enzyme drives the active proton transport from the interior of the mitochondria to Asp-51 across the enzyme via a water channel and a hydrogen-bond network, located in tandem, and that the enzyme reduction induces proton ejection from the aspartate to the mitochondrial exterior. A peptide bond in the hydrogen-bond network critically inhibits reverse proton transfer through the network. A redox-coupled change in the capacity of the water channel, induced by the hydroxyfarnesylethyl group of the low-spin heme, suggests that the channel functions as an effective proton-collecting region. Infrared results indicate that the conformation of Asp-51 is controlled only by the oxidation state of the low-spin heme. These results indicate that the low-spin heme drives the proton-pumping process.

Animals↗
PubMed1989

Replacement of aspartic residues 85, 96, 115, or 212 affects the quantum yield and kinetics of proton release and uptake by bacteriorhodopsin.

Recently, a number of aspartic acid mutants of bacteriorhodopsin have been shown to be defective in steady-state proton transport. Here we report time-resolved measurements of light-induced proton release and uptake for these mutants. Proton transfers between the protein and the aqueous phase were directly monitored by measuring changes in the bulk conductivity of a micellar solution of bacteriorhodopsin. For the Asp-96----Asn mutant, proton uptake was slowed by greater than 1 order of magnitude with no observable effect on the release step. For Asp-85----Asn, H+ uptake occurred with normal kinetics, but the yield was significantly lower compared with either the Asp-96----Asn mutant or wild type, especially at pH 6. Substitution of glutamate for Asp-85 or Asp-96 had smaller but detectable effects on the kinetics and quantum yield of proton movements. Both asparagine and glutamate substitutions of aspartates at positions 115 and 212 lowered the proton quantum yields. Of these, only the Asp-115----Asn mutant showed an effect on the proton release step, and only the Asp-212----Glu mutation decreased the proton uptake rate. These experiments imply an obligatory role for Asp-96 in H+ uptake in the normal operation of the bacteriorhodopsin proton pump. The results also indicate that the amino acid substitutions affect the kinetics of either H+ release or H+ uptake, but not both. This implies that the two steps occur independently of each other after initiation of the photocycle.

Asparagine↗
PubMed1995

Experimental evidence for hydrogen-bonded network proton transfer in bacteriorhodopsin shown by Fourier-transform infrared spectroscopy using azide as catalyst.

Experimental evidence for proton transfer via a hydrogen-bonded network in a membrane protein is presented. Bacteriorhodopsin's proton transfer mechanism on the proton uptake pathway between Asp-96 and the Schiff base in the M-to-N transition was determined. The slowdown of this transfer by removal of the proton donor in the Asp-96-->Asn mutant can be accelerated again by addition of small weak acid anions such as azide. Fourier-transform infrared experiments show in the Asp-96-->Asn mutant a transient protonation of azide bound to the protein in the M-to-N transition and, due to the addition of azide, restoration of the IR continuum band changes as seen in wild-type bR during proton pumping. The continuum band changes indicate fast proton transfer on the uptake pathway in a hydrogen-bonded network for wild-type bR and the Asp-96-->Asn mutant with azide. Since azide is able to catalyze proton transfer steps also in several kinetically defective bR mutants and in other membrane proteins, our finding might point to a general element of proton transfer mechanisms in proteins.

Amino Acid Sequence↗
PubMed1995

Proton transport by a bacteriorhodopsin mutant, aspartic acid-85-->asparagine, initiated in the unprotonated Schiff base state.

At alkaline pH the bacteriorhodopsin mutant D85N, with aspartic acid-85 replaced by asparagine, is in a yellow form (lambda max approximately 405 nm) with a deprotonated Schiff base. This state resembles the M intermediate of the wild-type photocycle. We used time-resolved methods to show that this yellow form of D85N, which has an initially unprotonated Schiff base and which lacks the proton acceptor Asp-85, transports protons in the same direction as wild type when excited by 400-nm flashes. Photoexcitation leads in several milliseconds to the formation of blue (630 nm) and purple (580 nm) intermediates with a protonated Schiff base, which decay in tens of seconds to the initial state (400 nm). Experiments with pH indicator dyes show that at pH 7, 8, and 9, proton uptake occurs in about 5-10 ms and precedes the slow release (seconds). Photovoltage measurements reveal that the direction of proton movement is from the cytoplasmic to the extracellular side with major components on the millisecond and second time scales. The slowest electrical component could be observed in the presence of azide, which accelerates the return of the blue intermediate to the initial yellow state. Transport thus occurs in two steps. In the first step (milliseconds), the Schiff base is protonated by proton uptake from the cytoplasmic side, thereby forming the blue state. From the pH dependence of the amplitudes of the electrical and photocycle signals, we conclude that this reaction proceeds in a similar way as in wild type--i.e., via the internal proton donor Asp-96. In the second step (seconds) the Schiff base deprotonates, releasing the proton to the extracellular side.

Asparagine↗
PubMed1998

The proton collecting function of the inner surface of cytochrome c oxidase from Rhodobacter sphaeroides.

The experiments presented in this study address the problem of how the cytoplasmic surface (proton-input side) of cytochrome c oxidase interacts with protons in the bulk. For this purpose, the cytoplasmic surface of the enzyme was labeled with a fluorescein (Flu) molecule covalently bound to Cys223 of subunit III. Using the Flu as a proton-sensitive marker on the surface and phiOH as a soluble excited-state proton emitter, the dynamics of the acid-base equilibration between the surface and the bulk was measured in the time-resolved domain. The results were analyzed by using a rigorous kinetic analysis that is based on numeric integration of coupled nonliner differential rate equations in which the rate constants are used as adjustable parameters. The analysis of 11 independent measurements, carried out under various initial conditions, indicated that the protonation of the Flu proceeds through multiple pathways involving diffusion-controlled reactions and proton exchange among surface groups. The surface of the protein carries an efficient system made of carboxylate and histidine moieties that are sufficiently close to each other as to form a proton-collecting antenna. It is the passage of protons among these sites that endows cytochrome c oxidase with the capacity to pick up protons from the buffered cytoplasmic matrix within a time frame compatible with the physiological turnover of the enzyme.

Electron Transport Complex IV↗
PubMed2003

Essential glycine in the proton channel of Escherichia coli transhydrogenase.

The nicotinamide nucleotide transhydrogenases of mitochondria and bacteria are proton pumps that couple hydride ion transfer between NAD(H) and NADP(H) bound, respectively, to extramembranous domains I and III, to proton translocation by the membrane-intercalated domain II. Previous experiments have established the involvement of three conserved domain II residues in the proton pumping function of the enzyme: His91, Ser139, and Asn222, located on helices 9, 10, and 13, respectively. Eight highly conserved domain II glycines in helices 9, 10, 13, and 14 were mutated to alanine, and the mutant enzymes were assayed for hydride transfer between domains I and III and for proton translocation by domain II. One of the glycines on helix 14, Gly252, was further mutated to Cys, Ser, Thr, and Val, expression levels of the mutant enzymes were evaluated, and each was purified and assayed. The results show that Gly252 is essential for function and support a model for the proton channel composed of helices 9, 10, 13, and 14. Gly252 would allow spatial proximity of His91, Ser139, and Asn222 for proton conductance within the channel. Gly252 mutants are distinguished by high levels of cyclic transhydrogenation activity in the absence of added NADP(H) and by complete loss of proton pumping activity. The purified G252A mutant has <1% proton translocation and reverse transhydrogenation activity, retains 0.9 mol of NADP(H) per domain III, and has 96% intrinsic cyclic transhydrogenation activity, which does not exceed 100% upon the addition of NADP(H). These properties imply that Gly252 mutants exhibit a native-like domain II conformation while blocking proton translocation and coupled exchange of NADP(H) in domain III.

Alanine↗
PubMed1997

Effect of pyrrolidine dithiocarbamate on photo-induced proton transport through chloroplast membranes.

pH changes produced by photo-induced proton transport through chloroplast membranes in spinach were measured by a glass microelectrode. Effect of pyrrolidine dithiocarbamate on proton translocation through chloroplast membranes has been studied. Kinetic analysis of proton translocation shows that the rate is reduced as the carbamate concentration increases. The rate of proton uptake follows first-order kinetics and diminishes with increasing carbamate concentrations. The outward leakage of accumulated protons through thylakoid membranes in the dark also decreases likewise. However, the leakage of protons takes a much longer time. Pyrrolidine dithiocarbamate is an effective inhibitor of proton transport through chloroplast membranes. The results suggest that the photo-induced proton translocation is regulated by conformation change in the membrane. Higher concentration of carbamate disrupts the tertiary conformation of the membrane. The inhibition of proton transport would affect ATPase function; thus, an excess use or accumulation of pyrrolidine thiocarbamate may compromise ATP production.

Chloroplasts↗
PubMed1991

Effects of external protons on single cardiac sodium channels from guinea pig ventricular myocytes.

The effects of external protons on single sodium channel currents recorded from cell-attached patches on guinea pig ventricular myocytes were investigated. Extracellular protons reduce single channel current amplitude in a dose-dependent manner, consistent with a simple rapid channel block model where protons bind to a site within the channel with an apparent pKH of 5.10. The reduction in single channel current amplitude by protons is voltage independent between -70 and -20 mV. Increasing external proton concentration also shifts channel gating parameters to more positive voltages, consistent with previous macroscopic results. Similar voltage shifts are seen in the steady-state inactivation (h infinity) curve, the time constant for macroscopic current inactivation (tau h), and the first latency function describing channel activation. As pHo decreases from 7.4 to 5.5 the midpoint of the h infinity curve shifts from -107.6 +/- 2.6 mV (mean +/- SD, n = 16) to -94.3 +/- 1.9 mV (n = 3, P less than 0.001). These effects on channel gating are consistent with a reduction in negative surface potential due to titration of negative external surface charge. The Gouy-Chapman-Stern surface charge model incorporating specific proton binding provides an excellent fit to the dose-response curve for the shift in the midpoint of the h infinity curve with protons, yielding an estimate for total negative surface charge density of -1e/490 A2 and a pKH for proton binding of 5.16. By reducing external surface Na+ concentration, titration of negative surface charge can also quantitatively account for the reduction in single Na+ channel current amplitude, although we cannot rule out a potential role for channel block. Thus, titration by protons of a single class of negatively charged sites may account for effects on both single channel current amplitude and gating.

Animals↗
PubMed1993

Current developments in proton therapy: a review.

The use of high-energy protons in radiotherapy was first proposed in 1946. In the last decade there has been a significant growth in the number of centres using protons in the treatment of malignant and non-malignant disease. To date (January 1993) a total of more than 11,500 patients have been treated world-wide. Encouraging clinical results have been reported in the literature. The purpose of this article is to outline the advantages of proton beams and to review current developments in physics and engineering applied to the field of proton therapy with particular emphasis on proton accelerator technology and the development of proton therapy facilities. The production of clinically useful beams is discussed and the relative merits of different treatment systems compared. Reference is also made to the factors affecting the absorbed dose in a patient and to proton radiobiology together with the results of studies of comparisons of treatment planning with protons with that using conventional photon therapy. The dosimetry of proton beams is also reviewed.

Humans↗
PubMed1999

Secondary electron fluence perturbation by high-Z interfaces in clinical proton beams: a Monte Carlo study.

Fluence perturbation of secondary electrons from clinical proton beams (50-250 MeV) by thin high-Z planar interfaces was studied with Monte Carlo simulations. Starting from monoenergetic proton pencil beams, proton depth doses and proton fluence spectra were calculated, both in homogeneous water and near thin high-Z interfaces by using the proton transport Monte Carlo code PTRAN. This code was modified extensively to enable modelling of proton transport in non-homogeneous geometries. From the proton fluence spectra in water and in the interface materials, electron generation spectra were calculated analytically and were then used as input for an electron transport calculation with the Monte Carlo code EGS4/PRESTAII to obtain electron doses and electron fluence spectra. The interface materials used in the study were graphite, Al, Ti, Cu, Sn and Au. We found significant electron fluence perturbations on both sides of the planar interfaces, resulting in an electron dose increase upstream and a decrease downstream from the interfaces, with the magnitude of the effect depending strongly on the atomic number of the interface. For the most extreme case studied, 250 MeV protons and a gold interface, we obtained an electron dose increase of 41% upstream of the interface and a decrease of 15% downstream with both perturbations having a spatial extent of about 700 microm. The total dose perturbation due to this effect amounts to a 5% increase upstream and a 2% decrease downstream. A detailed analysis of dose and fluence perturbation is presented for a wide range of materials and proton energies.

Electrons↗
PubMed2005

A particle track-repeating algorithm for proton beam dose calculation.

A particle track-repeating algorithm has been developed for proton beam dose calculation for radiotherapy. Monoenergetic protons with 250 MeV kinetic energy were simulated in an infinite water phantom using the GEANT3 Monte Carlo code. The changes in location, angle and energy for every transport step and the energy deposition along the track were recorded for the primary protons and all secondary particles. When calculating dose for a patient with a realistic proton beam, the pre-generated particle tracks were repeated in the patient geometry consisting of air, soft tissue and bone. The medium and density for each dose scoring voxel in the patient geometry were derived from patient CT data. The starting point, at which a proton track was repeated, was determined according to the incident proton energy. Thus, any protons with kinetic energy less than 250 MeV can be simulated. Based on the direction of the incident proton, the tracks were first rotated and for the subsequent steps, the scattering angles were simply repeated for air and soft tissue but adjusted properly based on the scattering power for bone. The particle step lengths were adjusted based on the density for air and soft tissue and also on the stopping powers for bone while keeping the energy deposition unchanged in each step. The difference in nuclear interactions and secondary particle generation between water and these materials was ignored. The algorithm has been validated by comparing the dose distributions in uniform water and layered heterogeneous phantoms with those calculated using the GEANT3 code for 120, 150, 180 and 250 MeV proton beams. The differences between them were within 2%. The new algorithm was about 13 times faster than the GEANT3 Monte Carlo code for a uniform phantom geometry and over 700 times faster for a heterogeneous phantom geometry.

Algorithms↗
PubMed1999

Safety profile of the proton-pump inhibitors.

The adverse effect profile of proton-pump inhibitors is presented. The proton-pump inhibitors are a well-tolerated class of drugs. The most common adverse events of headache, diarrhea, and nausea have been reported in fewer than 5% of patients treated with lansoprazole or omeprazole. The frequency of these adverse events with the two proton-pump inhibitors is comparable to that of placebo and histamine H2-receptor antagonists. Few clinically important interactions have been observed between proton-pump inhibitors and other drugs metabolized by the cytochrome P-450 system. The interaction potential should be considered when drugs with a narrow therapeutic window, such as phenytoin, warfarin, and theophylline, are used concomitantly with proton-pump inhibitors. Theoretical concerns about the consequences of chronic administration of proton-pump inhibitors, such as the impact of sustained hypergastrinemia on gastric morphology and the development of atrophic gastritis, have been dismissed. While increased gastrin levels are observed among patients taking proton-pump inhibitors, for the majority they remain within the normal range. After long-term use of the drugs, patients do not appear to be at increased risk of atrophic gastritis or gastric cancer. Helicobacter pylori infection, rather than acid suppression, may be the more important factor for the development of atrophic gastritis. Bacterial overgrowth and altered nutrient absorption resulting from sustained hypochlorhydria induced by chronic administration of proton-pump inhibitors have not been realized as clinical concerns. Not only are proton-pump inhibitors well tolerated during short-term administration, but there also do not appear to be clinically important adverse sequelae associated with their long-term use.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Methods of translating NMR proton distances into their corresponding heavy atom distances for protein structure prediction with limited experimental data.

This paper proposes a strategy to translate experimental 1H NMR proton distance restraints into their corresponding heavy atom distance restraints for the purpose of protein structure prediction. The relationships between interproton distances and the corresponding heavy atom distances are determined by studying well-resolved X-ray protein structures. The data from the interproton distances of amide protons, alpha-protons, beta-protons and side chain methyl protons are plotted against the corresponding heavy atoms in scatter plots and then fitted with linear equations for lower bounds, upper bounds and optimal fits. We also transform the scatter plots into two-dimensional heat maps and three-dimensional histograms, which identify the regions where data points concentrate. The common interproton distances between amide protons, alpha-protons, beta-protons in alpha-helices, anti-parallel beta-sheets and parallel beta-sheets are also tabulated. We have found several patterns emerging from the distance relationships between heavy atom pairs and their corresponding proton pairs. All our upper bound, lower bound and optimal fit results for translating the interproton distance into their corresponding heavy atom distances are tabulated.

Algorithms↗