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PubMed1980

On the mechanics of chromosomal aberrations: a study with single and multiple spatially-associated protons.

A unique radiation configuration, triads of protons, where mean separation between protons was controlled to be about 0.2 microns, has been used to irradiate Chinese hamster V79 cells. These triads of accelerated particles were more effective at producing chromosomal aberrations than randomly incident particles. Cells were irradiated with either single or three associated protons, with each proton depositing energy intracellularly at an LET of about 30 keV per micron. The associated protons were produced from accelerated molecular ions (H3+) that dissociated into atomic ions in a 6 mu Mylar foil on which the cells were growing, becoming triads of particles separated by a mean of about 0.2 microns in the cell nuclei. Chromosomal aberrations were scored from cells accumulated with colcemid over hourly intervals after irradiation. Those cells closest to mitosis (late G2) were the most sensitive to radiation, while overall "triple" protons were 52% more effective than single protons in producing aberrations. Only 10% of particles incident in nuclei resulted in an effect for the most sensitive period (late G2) dropping to 2% for the least sensitive period (early S--late G1). The frequencies of chromatid deletions declined dramatically with time post-irradiation, with isochromatid deletions less so and the frequencies of chromatid interchanges comparatively unchanged. Chromatid deletions and isochromatid deletions were often subtantially increased after "triple" proton irradiation, with the frequencies of chromatid interchanges less effected. This implies that both chromatid and isochromatid deletions can readily result from interactions between pairs of induced lesions about 0.2 microns apart. Achromatic lesions (gaps) were numerically equivalent after both irradiations implying a single lesion production mode. Results are compatible with there being a substantial short range component of interaction (less than 0.1 microns) between damaged sites, with a long range component of interaction extending to a few tenths of a micrometer.

Animals↗
PubMed1995

Proton inhibition of [3H]resiniferatoxin binding to vanilloid (capsaicin) receptors in rat spinal cord.

Protons and capsaicin activate overlapping subsets of sensory nerves by opening ion conductances of similar properties. We have used the [3H]resiniferatoxin binding assay utilizing rat spinal cord membranes to elucidate the possible interaction of protons at the vanilloid (capsaicin) receptor. Using low pH (pH 6.0 and pH 5.0) buffers, a time-dependent gradual decrease was observed in specific resiniferatoxin binding. Protons inhibited resiniferatoxin binding with an IC50 of pH 5.3 +/- 0.1. In experiments in which the concentration of [3H]resiniferatoxin was varied, protons reduced the Bmax value by approximately 40% with a corresponding 2-fold decrease in affinity. No change however, was observed in binding cooperativity (the Hill coefficients were 1.7 +/- 0.1 and 1.6 +/- 0.2 in the presence of pH 7.4 and pH 5.0 buffers, respectively). These changes in binding parameters are consistent with a non-competitive or, alternatively, mixed inhibitory mechanism. The remaining resiniferatoxin binding sites bound capsaicin with an affinity (Ki = 5.0 +/- 1.0 microM) very similar to that determined in the presence of a pH 7.4 buffer (Ki = 3.0 +/- 1.5 microM). A cyclooxygenase inhibitor, indomethacin (up to 10 microM), did not prevent the action of protons on resiniferatoxin binding; neither was it mimicked by prostanoids (prostaglandin I2 and E1, both at 100 microM). We conclude that protons interact at vanilloid receptors in the rat spinal cord; this interaction is either non-competitive or mixed in nature, and probably is not related to prostanoid generation. Protons and/or putative proton-generated mediators might represent endogenous modulators of the vanilloid receptor.

Animals↗
PubMed2006

Towards the mechanism of proton pumping by the haem-copper oxidases.

The haem-copper oxidases comprise a large family of enzymes that is widespread among aerobic organisms. These remarkable membrane-bound proteins catalyse the respiratory reduction of dioxygen to water, and conserve free energy from this reaction by operating as proton pumps. The mechanism of redox-dependent proton translocation has been elusive despite the availability of high resolution crystal structures from several oxidases. Here, we discuss some recent as well as some older results that may shed light on this mechanism. We conclude that proton-pumping is initiated by vectorial proton transfer from a conserved glutamic acid (Glu242 in the bovine enzyme) to a proton acceptor above the haem groups, and that this primary event is mechanistically coupled to electron transfer from haem a to the binuclear haem a3/CuB centre. Subsequently, Glu242 is reprotonated from the negatively charged side of the membrane. Next this proton is transferred to the binuclear site to complete the chemistry, Glu242 is reprotonated once more, and the "prepumped" proton is ejected on the opposite side of the membrane. The different kinetics of electron-coupled proton transfer in different steps of the catalytic cycle may be related to differences in the driving force due to different Em values of the electron acceptor in the binuclear site.

Catalysis↗
PubMed2004

Effects of palmitic acid and cholesterol on proton transport across black lipid membranes.

We studied the effect of palmitic acid (PA) and cholesterol (approximately 17 wt.%) on proton translocation across asolectin (charged) and diphytanoylphosphatidylcholine (DPhPC, neutral) black lipid membranes (BLMs). Potential difference (PD), short circuit current (SCC), and conductance (G(total)) were measured with a digital electrometer. Membranes were exposed to pH gradients (0.4-2.0 units), followed by PA addition to bath (symmetrically, 40-65 microM). The membrane conductive pathway was subdivided into an unspecific and a proton-related routes. A computer program estimated the conductances (G(un) and G(H)) of the two pathways from the measured parameters. No significant differences in proton selectivity were found between DPhPC membranes and DPhPC/cholesterol membranes. By contrast, cholesterol incorporation into asolectin increases membranes selectivity to proton. Cholesterol dramatically reduced G(un) reflecting, probably, its ability of inducing order in lipid chains. In asolectin membranes, PA increases proton selectivity, probably by acting as a proton shuttle according to the model proposed by Kamp and et al. [Biochemistry 34 (1995) 11928]. Cholesterol incorporation into asolectin membranes eliminates the PA-induced increase in proton selectivity. In DPhPC and DPhPC/cholesterol membranes, PA does not affect proton selectivity. These results are discussed in terms of the presence of cardiolipin (CL) in asolectin, cholesterol/PA interactions, and cholesterol order-inducing effects on acyl-chains.

Cell Membrane↗
PubMed2005

The early effect of proton pump inhibitor therapy on the accuracy of the 13C-urea breath test.

BACKGROUND: The intake of proton pump inhibitors may interfere with the reliability of the urea breath test. AIM: Prospective study to assess the accuracy of the urea breath test during the first days of therapy with proton pump inhibitors. PATIENTS: Thirty patients who needed to start proton pump inhibitors therapy and 53 volunteers. METHODS: A 13C-urea breath test was performed respectively before starting proton pump inhibitors therapy and every morning before its intake up until 10 days. The test was considered positive for values of 13CO2 > or = 3.0% delta over baseline. The coefficient of reproducibility for 95% interval of confidence of the urea breath test was calculated in both groups. RESULTS: Of the 30 patients receiving proton pump inhibitors, 47% were positive for Helicobacter pylori. Among these, 43% developed false negative breath tests in the first 10 days. False positive results occurred in 37.5% of H. pylori-negative subjects in the first 10 days. The coefficient of reproducibility of the urea breath test was significantly higher in the group treated with proton pump inhibitors (11.0 versus 1.8 for the control group, p < 0.0001). CONCLUSION: The intake of proton pump inhibitors impairs the accuracy of the 13C-urea breath test. False negative and false positive 13C-urea breath tests are common, occur as soon as after 1 day and increase with prolonged duration of treatment. The coefficient of reproducibility of the test in patients receiving proton pump inhibitors is not acceptable for clinical purpose and the test should not be performed once the medication has been started.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2005

Proton affinity of beta-oxalylaminoalanine (BOAA): incorporation of direct entropy correction into the single-reference kinetic method.

A new version of the single-reference-extended kinetic method is presented in which direct entropy correction is incorporated. Results of calibration experiments with the monodentate base pyridine and the bidentate base ethylenediamine are presented for which the method provides proton affinities in excellent agreement with published values and reasonable predictions for the protonation entropies. The method is then used to determine the proton affinity and protonation entropy of the non-protein amino acid beta-oxalylaminoalanine (BOAA). The PA of BOAA is found to be 933.1 +/- 7.8 kJ/mol and a prediction for the protonation entropy of -39 J mol(-1) K(-1) is also obtained, indicating a significant degree of intramolecular hydrogen bonding in the protonated form. These results are supported by hybrid density functional theory calculations at the B3LYP/6-311++G**//B3LYP/6-31+G* level. They indicate that the preferred site of protonation is the alpha-nitrogen atom (PA = 935.0 kJ/mol) and that protonated BOAA has a strong hydrogen bond between the hydrogen on the alpha-amino group and one of the carbonyl oxygen atoms on the side chain.

Amino Acids, Diamino↗
PubMed2003

The mechanism of proton exclusion in the aquaporin-1 water channel.

Aquaporins are efficient, yet strictly selective water channels. Remarkably, proton permeation is fully blocked, in contrast to most other water-filled pores which are known to conduct protons well. Blocking of protons by aquaporins is essential to maintain the electrochemical gradient across cellular and subcellular membranes. We studied the mechanism of proton exclusion in aquaporin-1 by multiple non-equilibrium molecular dynamics simulations that also allow proton transfer reactions. From the simulations, an effective free energy profile for the proton motion along the channel was determined with a maximum-likelihood approach. The results indicate that the main barrier is not, as had previously been speculated, caused by the interruption of the hydrogen-bonded water chain, but rather by an electrostatic field centered around the fingerprint Asn-Pro-Ala (NPA) motif. Hydrogen bond interruption only forms a secondary barrier located at the ar/R constriction region. The calculated main barrier height of 25-30 kJ mol(-1) matches the barrier height for the passage of protons across pure lipid bilayers and, therefore, suffices to prevent major leakage of protons through aquaporins. Conventional molecular dynamics simulations additionally showed that negatively charged hydroxide ions are prevented from being trapped within the NPA region by two adjacent electrostatic barriers of opposite polarity.

Animals↗
PubMed2006

Crystal structures of archaerhodopsin-1 and -2: Common structural motif in archaeal light-driven proton pumps.

Archaerhodopsin-1 and -2 (aR-1 and aR-2) are light-driven proton pumps found in Halorubrum sp. aus-1 and -2, which share 55-58% sequence identity with bacteriorhodopsin (bR), a proton pump found in Halobacterium salinarum. In this study, aR-1 and aR-2 were crystallized into 3D crystals belonging to P4(3)2(1)2 (a = b = 128.1 A, c = 117.6 A) and C222(1) (a = 122.9 A, b = 139.5 A, c = 108.1 A), respectively. In both the crystals, the asymmetric unit contains two protein molecules with slightly different conformations. Each subunit is composed of seven helical segments as seen in bR but, unlike bR, aR-1 as well as aR-2 has a unique omega loop near the N terminus. It is found that the proton pathway in the extracellular half (i.e. the proton release channel) is more opened in aR-2 than in aR-1 or bR. This structural difference accounts for a large variation in the pKa of the acid purple-to-blue transition among the three proton pumps. All the aromatic residues surrounding the retinal polyene chain are conserved among the three proton pumps, confirming a previous argument that these residues are required for the stereo-specificity of the retinal isomerization. In the cytoplasmic half, the region surrounded by helices B, C and G is highly conserved, while the structural conservation is very low for residues extruded from helices E and F. Structural conservation of the hydrophobic residues located on the proton uptake pathway suggests that their precise arrangement is necessary to prevent a backward flow of proton in the presence of a large pH gradient and membrane potential. An empty cavity is commonly seen in the vicinity of Leu93 contacting the retinal C13 methyl. Existence of such a cavity is required to allow a large rotation of the side-chain of Leu93 at the early stage of the photocycle, which has been shown to accompany water translocation across the Schiff base.

Amino Acid Sequence↗
PubMed2000

Proton transfer from glutamate 286 determines the transition rates between oxygen intermediates in cytochrome c oxidase.

We have investigated the electron-proton coupling during the peroxy (P(R)) to oxo-ferryl (F) and F to oxidised (O) transitions in cytochrome c oxidase from Rhodobacter sphaeroides. The kinetics of these reactions were investigated in two different mutant enzymes: (1) ED(I-286), in which one of the key residues in the D-pathway, E(I-286), was replaced by an aspartate which has a shorter side chain than that of the glutamate and, (2) ML(II-263), in which the redox potential of Cu(A) is increased by approximately 100 mV, which slows electron transfer to the binuclear centre during the F-->O transition by a factor of approximately 200. In ED(I-286) proton uptake during P(R)-->F was slowed by a factor of approximately 5, which indicates that E(I-286) is the proton donor to P(R). In addition, in the mutant enzyme the F-->O transition rate displayed a deuterium isotope effect of approximately 2.5 as compared with approximately 7 in the wild-type enzyme. Since the entire deuterium isotope effect was shown to be associated with a single proton-transfer reaction in which the proton donor and acceptor must approach each other (M. Karpefors, P. Adelroth, P. Brzezinski, Biochemistry 39 (2000) 6850), the smaller deuterium isotope effect in ED(I-286) indicates that proton transfer from E(I-286) determines the rate also of the F-->O transition. In ML(II-263) the electron-transfer to the binuclear centre is slower than the intrinsic proton-transfer rate through the D-pathway. Nevertheless, both electron and proton transfer to the binuclear centre displayed a deuterium isotope effect of approximately 8, i.e., about the same as in the wild-type enzyme, which shows that these reactions are intimately coupled.

Deuterium↗
PubMed2001

Mitochondrial proton leak: a role for uncoupling proteins 2 and 3?

In mitochondria ATP synthesis is not perfectly coupled to oxygen consumption due to proton leak across the mitochondrial inner membrane. Quantitative studies have shown that proton leak contributes to approximately 25% of the resting oxygen consumption of mammals. Proton leak plays a role in accounting for differences in basal metabolic rate. Thyroid studies, body mass studies, phylogenic studies and obesity studies have all shown that increased mass-specific metabolic rate is linked to increased mitochondrial proton leak. The mechanism of the proton leak is unclear. Evidence suggests that proton leak occurs by a non-specific diffusion process across the mitochondrial inner membrane. However, the high degree of sequence homology of the recently cloned uncoupling proteins UCP 2 and UCP 3 to brown adipose tissue UCP 1, and their extensive tissue distribution, suggest that these novel uncoupling proteins play a role in proton leak. Early indications from reconstitution experiments and several in vitro expression studies suggest that the novel uncoupling proteins uncouple mitochondria. Furthermore, mice overexpressing UCP 3 certainly show a phenotype consistent with increased metabolism. The evidence for a role for these novel UCPs in mitochondrial proton leak is reviewed.

Adipose Tissue, Brown↗
PubMed2002

Molecular dynamics simulation of proton transport through the influenza A virus M2 channel.

The structural and dynamical properties of a solvated proton in the influenza A virus M2 channel are studied using a molecular dynamics (MD) simulation technique. The second-generation multi-state empirical valence bond (MS-EVB2) model was used to describe the interaction between the excess proton and the channel environment. Solvation structures of the excess proton and its mobility characteristics along the channel were determined. It was found that the excess proton is capable of crossing the channel gate formed by the ring of four histidine residues even though the gate was only partially open. Although the hydronium ion itself did not cross the channel gate by traditional diffusion, the excess proton was able to transport through the ring of histidine residues by hopping between two water molecules located at the opposite sides of the gate. Our data also indicate that the proton diffusion through the channel may be correlated with the changes in channel conformations. To validate this observation, a separate simulation of the proton in a "frozen" channel has been conducted, which showed that the proton mobility becomes inhibited.

Biological Transport↗
PubMed2004

Proton transfer dynamics at the membrane/water interface: dependence on the fixed and mobile pH buffers, on the size and form of membrane particles, and on the interfacial potential barrier.

Crossing the membrane/water interface is an indispensable step in the transmembrane proton transfer. Elsewhere we have shown that the low dielectric permittivity of the surface water gives rise to a potential barrier for ions, so that the surface pH can deviate from that in the bulk water at steady operation of proton pumps. Here we addressed the retardation in the pulsed proton transfer across the interface as observed when light-triggered membrane proton pumps ejected or captured protons. By solving the system of diffusion equations we analyzed how the proton relaxation depends on the concentration of mobile pH buffers, on the surface buffer capacity, on the form and size of membrane particles, and on the height of the potential barrier. The fit of experimental data on proton relaxation in chromatophore vesicles from phototropic bacteria and in bacteriorhodopsin-containing membranes yielded estimates for the interfacial potential barrier for H(+)/OH(-) ions of approximately 120 meV. We analyzed published data on the acceleration of proton equilibration by anionic pH buffers and found that the height of the interfacial barrier correlated with their electric charge ranging from 90 to 120 meV for the singly charged species to >360 meV for the tetra-charged pyranine.

Bacterial Chromatophores↗
PubMed1994

Alpha-helical hydrophobic polypeptides form proton-selective channels in lipid bilayers.

Proton translocation is important in membrane-mediated processes such as ATP-dependent proton pumps, ATP synthesis, bacteriorhodopsin, and cytochrome oxidase function. The fundamental mechanism, however, is poorly understood. To test the theoretical possibility that bundles of hydrophobic alpha-helices could provide a low energy pathway for ion translocation through the lipid bilayer, polyamino acids were incorporated into extruded liposomes and planar lipid membranes, and proton translocation was measured. Liposomes with incorporated long-chain poly-L-alanine or poly-L-leucine were found to have proton permeability coefficients 5 to 7 times greater than control liposomes, whereas short-chain polyamino acids had relatively little effect. Potassium permeability was not increased markedly by any of the polyamino acids tested. Analytical thin layer chromatography measurements of lipid content and a fluorescamine assay for amino acids showed that there were approximately 135 polyleucine or 65 polyalanine molecules associated with each liposome. Fourier transform infrared spectroscopy indicated that a major fraction of the long-chain hydrophobic peptides existed in an alpha-helical conformation. Single-channel recording in both 0.1 N HCl and 0.1 M KCl was also used to determine whether proton-conducting channels formed in planar lipid membranes (phosphatidylcholine/phosphatidylethanolamine, 1:1). Poly-L-leucine and poly-L-alanine in HCl caused a 10- to 30-fold increase in frequency of conductive events compared to that seen in KCl or by the other polyamino acids in either solution. This finding correlates well with the liposome observations in which these two polyamino acids caused the largest increase in membrane proton permeability but had little effect on potassium permeability. Poly-L-leucine was considerably more conductive than poly-L-alanine due primarily to larger event amplitudes and, to a lesser extent, a higher event frequency. Poly-L-leucine caused two populations of conductive events, one in the 0.1-0.5 pA range, and one in the 1.0-5.0 pA range, whereas nearly all events caused by poly-L-alanine were in the 0.1-0.5 pA range at an applied voltage of +60 mV. The channel-like activity appeared to switch between conductive and nonconductive states, with most open-times in the range of 50-200 ms. We conclude that hydrophobic polyamino acids produce proton-conducting defects in lipid bilayers that may be used to model functional proton channels in biological membranes.

Alamethicin↗
PubMed1995

Relationship of proton release at the extracellular surface to deprotonation of the schiff base in the bacteriorhodopsin photocycle.

The surface potential of purple membranes and the release of protons during the bacteriorhodopsin photocycle have been studied with the covalently linked pH indicator dye, fluorescein. The titration of acidic lipids appears to cause the surface potential to be pH-dependent and causes other deviations from ideal behavior. If these anomalies are neglected, the appearance of protons can be followed by measuring the absorption change of fluorescein bound to various residues at the extracellular surface. Contrary to widely held assumption, the activation enthalpies of kinetic components, deuterium isotope effects in the time constants, and the consequences of the D85E, F208R, and D212N mutations demonstrate a lack of direct correlation between proton transfer from the buried retinal Schiff base to D85 and proton release at the surface. Depending on conditions and residue replacements, the proton release can occur at any time between the protonation of D85 and the recovery of the initial state. We conclude that once D85 is protonated the proton release at the extracellular protein surface is essentially independent of the chromophore reactions that follow. This finding is consistent with the recently suggested version of the alternating access mechanism of bacteriorhodopsin, in which the change of the accessibility of the Schiff base is to and away from D85 rather than to and away from the extracellular membrane surface.

Bacteriorhodopsins↗
PubMed1996

Kinetic isotope effects reveal an ice-like and a liquid-phase-type intramolecular proton transfer in bacteriorhodopsin.

The mechanism of the intramolecular proton transfer in the membrane protein bacteriorhodopsin (bR) is studied. The kinetic isotope effects after H/D exchange were determined for the individual photocycle reactions and used as an indicator. Significant differences in the kinetic isotope effects are observed between the intramolecular proton transfer on the release and the uptake pathways. The results suggest a fast intramolecular proton transfer mechanism in the proton release pathway, which is similar to the one proposed for ice, where the rate limiting step is the proton movement within the H bond. However, the reactions in the intramolecular proton uptake pathway occur in a mechanism similar to the one suggested for liquid water, where the rate limiting step is given by a rotational rearrangement of H bonded network groups. We propose that the experimental evidence for a proton wire mechanism given here for bacteriorhodopsin is of general relevance also for other proton transporting proteins.

Bacteriorhodopsins↗
PubMed2003

Cost analysis of endoscopic antireflux procedures: endoluminal plication vs. radiofrequency coagulation vs. treatment with a proton pump inhibitor.

BACKGROUND: Both endoluminal gastroplication and radiofrequency coagulation of the lower esophageal sphincter and gastroesophageal junction (Stretta procedure) represent emerging endoscopic therapies for GERD. The economic impact of endotherapy for GERD has not been described. The aim of this study was to apply a decision analysis model to compare the costs of endoluminal gastroplication vs. the Stretta procedures vs. a proton pump inhibitor for treatment of GERD. A cost minimization approach was used. METHODS: Model entry criteria were GERD responsive to daily or twice daily administration of a proton pump inhibitor. Performance characteristics of endotherapy were determined from published data. The baseline probabilities for annual endotherapy failure rates (20%), partial failure rates (10%), and complication rates (1%) were varied through a plausible range by using sensitivity analysis. Cost data for endotherapy were calculated from per case instrumentation costs plus professional fees plus facility fees for ambulatory patient classification codes; cost of treatment with a proton pump inhibitor was based on national average wholesale price. The endpoint was sustained resolution of GERD symptoms. RESULTS: In patients requiring twice daily use of a proton pump inhibitor for symptom relief, endotherapy proves to be the most economical strategy after 17 months. If uniform endotherapy failure rates over time are assumed, medication regains superiority after 29 months. Sensitivity analysis revealed that a proton pump inhibitor remains the most economical option beyond 3 years, provided annual endotherapy failure rates remain greater than 20% (endoluminal gastroplication) or 19% (Stretta). Pharmacotherapy is the least costly approach, irrespective of time, if the daily cost of a proton pump inhibitor is less than $140 a month or endotherapy costs more than $3400. For patients in whom symptoms are relieved with once daily dosing with a proton pump inhibitor, medication remains the most economical option regardless of endotherapy failure rate. CONCLUSION: Endotherapy appears to offer an economical treatment option for patients requiring a proton pump inhibitor twice daily, with its cost superiority enduring for 2.5 years. More long-term follow-up data are required to determine the durability of the endotherapy benefit over time.

Catheter Ablation↗
PubMed2002

Ligand binding reveals protonation events at the active site of cytochrome c oxidase; is the K-pathway used for the transfer of H(+) or OH(-)?

We have investigated the CO-recombination kinetics after flash photolysis of CO from the "half-reduced" cytochrome c oxidase as a function of pH. In addition, the reaction was investigated in mutant enzymes in which Lys(I-362) and Ser(I-299), located approximately in the middle of the K-pathway and near the enzyme surface, respectively, were modified. Laser-flash induced dissociation of CO is followed by rapid internal electron transfer from heme a(3) to a. At pH>7 this electron transfer is associated with proton release to the bulk solution (tau congruent with 1 ms at pH 8). Thus, the CO-recombination kinetics reflects protonation events at the catalytic site. In the wild-type enzyme, below pH approximately 7, the main component in the CO-recombination displayed a rate of approximately 20 s(-1). Above pH approximately 7, a slow CO-recombination component developed with a rate that decreased from approximately 8 s(-1) at pH 8 to approximately 1 s(-1) at pH 10. This slow component was not observed with KM(I-362), while with the SD(I-299)/SG(I-299) mutant enzymes at each pH it was slower than with the wild-type enzyme. The results are interpreted in terms of proton release from H(2)O in the catalytic site after CO dissociation, followed by OH(-) binding to the oxidized heme a(3). The CO-recombination kinetics is proposed to be determined by the protonation rate of OH(-) and not dissociation of OH(-), i.e. the K-pathway transfers protons and not OH(-). With the KM(I-362) mutant enzyme the proton is not released, i.e. OH(-) is not formed. With the SD(I-299)/SG(I-299) mutant enzymes the proton is released, but both the release and uptake are slowed by the mutations. During reaction of the reduced enzyme with O(2), the H(2)O at the binuclear center is most likely involved as a proton donor in the O-O cleavage reaction.

Binding Sites↗
PubMed1996

Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: Conformal treatment planning with megavoltage X-rays and protons for medically inoperable patients with a large rectal cancer has been studied in an attempt to determine if there are advantages of using protons instead of X-rays. MATERIAL AND METHODS: Three dose plans were made for each of the six patients: one proton plan, including three beams covering the primary tumour and adjacent lymph nodes and three boost beams covering the primary tumour: one X-ray plan, eight beams including a boost with four beams and one mixed plan with four X-ray beams and a boost with three proton beams. A three dimensional treatment-planning systems, TMS, was used. The evaluation of the different plans was made by applying the biological models TCP and NTCP on the dose distributions in terms of dose-volume histograms. RESULTS: The comparison shows advantages of using protons instead of X-rays for all six patients, but in three of them, the advantage is only marginal. The dose-limiting organ at risk is the small bowel, but the proton plan and the mixed plan also spare the bladder and the femoral heads better. At 5% NTCP in any risk organ, the calculated mean TCP value for the six patients is increased by 14%-units with the proton plan and 8%-units with the mixed plan compared to X-rays only. CONCLUSIONS: Proton beam therapy has potential advantages when treating medically inoperable patients with a large rectal cancer over conventional X-ray therapy. Since the benefits are comparatively small, although clinically worthwhile, large randomised studies are needed.

Aged↗