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PubMed1994

Clinical and radiological evaluation of long-term results of stereotactic proton beam radiosurgery in patients with cerebral arteriovenous malformations.

Within a period of nearly 10 years, from October, 1980, to May, 1990, a total of 68 patients with a cerebral arteriovenous malformation (AVM) were referred to a radiosurgical center in the United States for stereotactic Bragg peak proton beam therapy. Radiosurgery was chosen as an alternative treatment, either because the AVM was considered to be of high surgical risk due to its size and/or location, or because the patient refused surgery. In 63 patients (92.6%), complete clinical and radiological follow-up examinations were available. Clinical and radiological long-term results were correlated to size and to the Spetzler-Martin scale of the AVM. With increasing size or higher grade on the Spetzler-Martin scale, the clinical results of proton beam therapy became progressively worse. Of 37 patients with an AVM between 3 and 6 cm in diameter, only one-third showed amelioration of their clinical symptoms, and two-thirds remained the same or even deteriorated after radiation treatment. The same results apply to patients with very large AVM's, of whom only one-third profited from proton beam therapy. Although 85.7% of the patients in Spetzler-Martin Grades I and II showed postirradiation amelioration of their clinical symptoms, this compares to only 54.2% of the patients in Grade III, and only 24% in Grade IV. In regard to the radiological results of proton beam therapy, complete obliteration during long-term observation was only detectable in 10 patients or 15.9%, which is less than one-sixth of the whole group of 63 patients. All of these obliterated AVM's were smaller than 3 cm. Almost 85% of the patients treated using stereotactic proton beam therapy did not show any angiographic change in the radiological appearance of their AVM. The results reported here indicate that radiosurgery using stereotactic proton beam therapy is ineffective for the treatment of medium- or large-sized AVM's and should not be recommended for patients harboring an AVM larger than 3 cm. If proton beam treatment is contemplated, it should be restricted to AVM's that are less than 3 cm in size and whose location makes them easily accessible only for proton beam therapy.

Adolescent↗
PubMed1979

Biological amine transport in chromaffin ghosts. Coupling to the transmembrane proton and potential gradients.

The effect of the transmembrane proton gradient (delta pH) and potential gradient (delta psi) upon the rate and extent of amine accumulation was investigated in chromaffin ghosts. The chromaffin ghosts were formed by hypo-osmotic lysis of isolated bovine chromaffin granules and extensive dialysis in order to remove intragranular binding components and dissipate the endogenous electrochemical gradients. Upon ATP addition to suspensions of chromaffin ghosts, a transmembrane proton gradient alone, a transmembrane gradient alone, or both, could be established, depending upon the compositions of the media in which the ghosts were formed and resuspended. When chloride was present in the medium, addition of ATP resulted in the generation of a transmembrane proton gradient, acidic inside of 1 pH unit (measured by [14C]methylamine distribution), and no transmembrane potential (measured by [14C]-thiocyanate distribution). When ATP was added to chromaffin ghosts suspended in a medium in which chloride was substituted by isethionate, a transmembrane potential, inside positive, of 45 mV and no transmembrane proton gradient, was measured. In each medium, the addition of agents known to affect proton or potential gradients, respectively, exerted a predictable mechanism of action. Accumulation of [14C]epinephrine or [14C]5-hydroxytryptamine was over 1 order of magnitude greater in the presence of the transmembrane proton gradient or the transmembrane potential than in the absence of any gradient and, moreover, was related to the magnitude of the proton or potential gradient in a dose-dependent manner. When ghosts were added to a medium containing chloride and isethionate, both a delta pH and delta psi could be generated upon addition of ATP. In this preparation, the maximal rate of amine accumulation was observed. The results indicate that amine accumulation into chromaffin ghosts can occur in the presence of either a transmembrane proton gradient, or a transmembrane potential gradient, and that the maximal rate of accumulation may exist when both components of the protonmotive force are present.

Adenosine Triphosphate↗
PubMed1981

Proton: substrate stoichiometries during active transport of biogenic amines in chromaffin ghosts.

The relationship between the electrochemical proton gradient (delta mu-H+) and the electrochemical gradient for biogenic amines (delta mu-A) was investigated in isolated chromaffin ghosts free of endogenous components and gradients. The addition of ATP to a ghost suspension resulted in the generation of a large proton concentration gradient (delta pH), acidic inside (measured by [14C]-methylamine distribution), and a large proton electrical gradient (delta psi), positive inside (measured by [14C]-thiocyanate distribution). In the presence of this large electrochemical proton gradient, the accumulation of [14C]5-hydroxytryptamine (serotonin) and other biogenic amines rapidly reached an apparent steady state level. Collapse of the proton gradients after steady state levels were achieved resulted in the efflux of the accumulated amines. Uptake in the presence of a delta psi alone produced an amine gradient equal to the magnitude of the delta psi, while in the presence of a delta pH alone biogenic amine distribution was equal to twice the magnitude of the delta pH. Using additions of ammonia or thiocyanate, it was possible to vary the magnitude of the electrochemical proton gradient over a wide range of values; the driving force for amine accumulation under these conditions was found to be equal to delta psi--2Z delta pH (where Z = 2.3 RT/F). The results, which provide unequivocal evidence for the primary role of the electrochemical proton gradient in the active transport of biogenic amines, are consistent with a model based on the chemiosmotic hypothesis, of an obligatory coupling of amine influx and proton efflux, mediated via a putative reserpine-sensitive translocator. Measurement of the stoichiometry of this coupling of H+ and amines permits conclusions concerning the molecular mechanism of amino accumulation.

Ammonia↗
PubMed1994

Protonation of nucleobase anions in gamma-irradiated DNA and model systems. Which DNA base is the ultimate sink for the electron?

Electron spin resonance (ESR) spectroscopy has been used to investigate irreversible protonations of the nucleobase anions in gamma-irradiated frozen aqueous solutions of dGMP-dCMP, polyG-polyC, poly[dGdC].poly[dGdC], dAMP-dTMP, poly[dAdT].poly-[dAdT] and DNA itself. Analysis of the ESR spectra at a dose of 22 kGy shows that fractional conversion of total radicals to carbon-protonated species on annealing is in the order: dAMP-dTMP (43%) > pdAdT = DNA (23%) > dGMP.dCMP (15%) > poly-dGdC.polydGdC (6%) > polyG.polyC (3%). Two hydrogen addition radicals make contributions to the polyG.polyC, poly-[dGdC].poly[dGdC] and dGMP.dCMP spectra in H2O on annealing. They are those formed by protonations at C6 of the cytosine anion radical, C(C6)H., and at C8 of the guanine anion radical, G(C8)H.. Computer analysis reveals that anion protonation reaction in dGMP.dCMP results in mainly C(C6)H., whereas protonation reaction in polyG.polyC and poly[dGdC].poly-[dGdC] yields mainly G(C8)H.. In dAMP.dTMP and poly[dAdT].poly[dAdT] as in DNA itself, the only DNA base found to undergo an irreversible protonation at a carbon site is thymine, resulting in T(C6)H.. The conversion of DNA anion to T(C6)H. is found to be dependent on dose. At low doses (5 kGy), about 30% conversion to T(C6)H. is found, whereas at high doses (94 kGy), only 13% conversion is found. The dose dependence is ascribed in part to ion radical recombinations whose probabilities are increased at high doses. A consideration of the rates of protonations of the purine and pyrimidine anion radicals as well as the differences in electron affinities suggest carbon protonation reactions of DNA base anions in irradiated stacked double-strand DNA at 37 degrees C would be predominantly at thymine and perhaps guanine, whereas in single-strand DNA all bases would contribute.

DNA↗
PubMed1993

Azotobacter vinelandii ferredoxin I. Aspartate 15 facilitates proton transfer to the reduced [3Fe-4S] cluster.

The [3Fe-4S]+/0 cluster of Azotobacter vinelandii ferredoxin I (AvFdI) has an unusually low and strongly pH-dependent reduction potential (E'0). The reduced cluster exists in two forms, depending upon pH, that exhibit substantially different magnetic circular dichroism (MCD) spectra. Recent studies have established that the MCD changes observed on decreasing the pH from 8.3 (alkaline form) to 6.0 (acid form) cannot be explained either by a change in spin state of the cluster (Stephens, P.J., Jensen, G.M., Devlin, F.J., Morgan, T.V., Stout, C. D., Martin, A.E., and Burgess, B.K. (1991) Biochemistry 30, 3200-3209) or by a major structural change (e.g. ligand exchange) (Stout, C.D. (1993) J. Biol. Chem. 268, 25920-25927). Here, we have examined the influence of aspartate 15 on the pH dependence of the spectroscopic and electrochemical properties of AvFdI by construction of a D15N mutant. Aspartate 15, which is salt-bridged to lysine 84 at the protein surface, is the closest ionizable residue to the [3Fe-4S] cluster. The results show that replacement of aspartate by asparagine results in an approximately 20-mV increase in E'0 for the [3Fe-4S]+/0 cluster at high pH concomitant with an approximately 0.8-pH unit decrease in the pK of the reduced form. The major pH dependence of E'0 is preserved as is the effect observed by MCD. These data eliminate the possibility that the MCD change is due to the presence of Asp-15 and support the conclusion that it originates in direct protonation of the [3Fe-4S]0 cluster, probably on a sulfide ion. Voltammetric studies show that interconversion between [3Fe-4S]+ and [3Fe-4S]0 at acidic pH involves rapid electron transfer followed by proton transfer (for reduction) and then proton transfer followed by electron transfer (for oxidation). Ionized aspartate 15 facilitates proton transfer. Thus, protonation and deprotonation are much slower for D15N relative to the native protein at pH > 5.5. Proton transfer reactions necessary for further reduction of the [3Fe-4S]0 cluster to the [3Fe-4S]- and [3Fe-4S]2- states are also retarded in D15N. The results suggest that the carboxylate-ammonium salt bridge afforded by Asp-15-Lys-84 conducts protons between the cluster and solvent H2O molecules. Overproduction of D15N FdI, but not native FdI, in A. vinelandii has a negative effect on the growth rate of the organism, suggesting that the rate of protonation or deprotonation of the [3Fe-4S]0 cluster may be important in vivo.

Amino Acid Sequence↗
PubMed1996

Reconstitution of lactate proton symport activity in plasma membrane vesicles from the yeast Candida utilis.

Lactic acid transport was studied in plasma membrane vesicles from the yeast Candida utilis IGC 3092 which were fused with liposomes containing cytochrome c oxidase. After the addition of an electron donor system, these hybrid membrane vesicles were able to generate a proton-motive force of about--150 mV, inside alkaline and negative. In vesicles prepared from lactic acid-grown cells, the uptake of labelled lactic acid, at pH 6.2, under energized conditions, was expressed by a kinetics consistent with the involvement of a mediated transport system. This carrier exhibited a substrate specificity pattern identical to the one found for the lactate-proton symport in intact cells. The transport of labelled lactic acid was accumulative and strongly sensitive to the effects of the protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, consistent with the involvement of the proton-motive force in acid uptake, hence with the presence of a proton symport for lactate. Dissipation of the transmembrane electric potential by valinomycin did not have a significant effect on lactate accumulation, whereas abolishing the transmembrane pH gradient (delta pH) by nigericin prevented the accumulation and led to a rapid efflux of the accumulated acid. The data support that the delta pH is the main component of the proton-motive force involved in the transport of the acid and its accumulation. The lactate-proton symport stoichiometry was 1:1, being independent of the pH. Vesicles prepared from glucose-grown cells did not display the capacity to transport and accumulate lactate. However, activity for the carrier was also reconstituted in vesicles obtained from glucose-grown cells after incubation in buffer containing lactic acid. These results were consistent with those obtained in intact cells, which demonstrated that the lactate-proton symport of the yeast C. utilis is inducible.

Biological Transport, Active↗
PubMed1988

Structural properties of the proton translocating complex of the clathrin-coated vesicle.

The clathrin-coated vesicle proton pump is a representative member of the new class of endomembrane proton ATPases that share an inhibitor profile which distinguishes them from classic F1F0 and E1E2-type proton pumps. The coated vesicle proton pump is a large (530 kDa) heteroligomer composed of eight polypeptides with molecular masses of 116, 70, 58, 40, 38, 34, 33 and 17 kDa. The 200-fold purified enzyme catalyses ATP-generated proton pumping when reconstituted in liposomes composed of pure lipids. Subunit function has been determined by partial reaction analysis of subunit and subcomplex activities. The isolated 17 kDa subunit, when co-reconstituted with bacteriorhodopsin, forms a dicyclohexylcarbodiimide-inhibitable proton channel. Selective removal of the 116 kDa subunit transforms the proton ATPase from a Mg2+-activatable to a Ca2+-activatable ATPase. Subsequent dissociation and reconstitution of subunits reveals that the 70, 58, 40 and 33 kDa components are required, in composite, to form a functional ATP-hydrolytic core, and that no single subunit or subcomplex deficient in these subunits can catalyse ATP hydrolysis.

Adenosine Triphosphate↗
PubMed2005

Proton beam therapy for hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND: Treatment modalities for patients with hepatocellular carcinoma (HCC) who have portal vein tumor thrombus (PVTT) are limited and controversial; furthermore, the prognosis for these patients is extremely poor. The authors conducted a retrospective review to determine the role of proton beam therapy in the treatment of patients who had HCC with PVTT. METHODS: Twelve patients with HCC who had tumor thrombus in the main trunk or major branches of the portal vein (clinical T3-T4N0M0) were treated with proton beam therapy. At the time they received proton beam irradiation, patients ranged in age from 42 years to 80 years (median, 62 years), and their tumors ranged in size from 40 mm to 110 mm (median, 60 mm) in greatest dimension. A total dose of 50-72 gray (Gy) (median, 55 Gy) in 10-22 fractions was delivered to the tumors, including PVTT. RESULTS: All tumors that were treated with proton beam therapy remained controlled at a median follow-up of 2.3 years (range, 0.3-7.3 years). Among 12 patients, 10 patients had new liver tumors outside the irradiated volume 0.1-2.4 years after proton beam therapy, and 3 patients also had distant metastases; consequently, 8 patients died of disease, and 2 patients were salvaged by further therapies. The remaining two patients were alive with no evidence of disease 4.3 years and 6.4 years after proton beam therapy. The progression-free survival rates were 67% at 2 years and 24% at 5 years. The median progression-free survival was 2.3 years. According to the Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group), therapy-related toxicity > or = Grade 3 was not observed. CONCLUSIONS: Proton beam therapy for patients with HCC who had PVTT was feasible and effective. It appeared to improve survival and local control significantly for these patients.

Adult↗
PubMed2006

Elementary steps of proton translocation in the catalytic cycle of cytochrome oxidase.

Proton translocation in the catalytic cycle of cytochrome c oxidase (CcO) proceeds sequentially in a four-stroke manner. Every electron donated by cytochrome c drives the enzyme from one of four relatively stable intermediates to another, and each of these transitions is coupled to proton translocation across the membrane, and to uptake of another proton for production of water in the catalytic site. Using cytochrome c oxidase from Paracoccus denitrificans we have studied the kinetics of electron transfer and electric potential generation during several such transitions, two of which are reported here. The extent of electric potential generation during initial electron equilibration between CuA and heme a confirms that this reaction is not kinetically linked to vectorial proton transfer, whereas oxidation of heme a is kinetically coupled to the main proton translocation events during functioning of the proton pump. We find that the rates and amplitudes in multiphase heme a oxidation are different in the OH-->EH and PM-->F steps of the catalytic cycle, and that this is reflected in the kinetics of electric potential generation. We discuss this difference in terms of different driving forces and relate our results, and data from the literature, to proposed mechanisms of proton pumping in cytochrome c oxidase.

Catalysis↗
PubMed2006

Triton X-100 can alter the temporal sequence of the light-driven proton pump of archaerhodopsin 4.

We report that Triton X-100 can alter the temporal sequence of the light-induced proton uptake and release of archaerhodopsin 4 (AR4), a proton pumping protein in a species of Halobacteria from a Tibetan salt lake. Under physiological conditions, AR4 isolated from the bacterium exhibits a reversed temporal order of proton release and uptake compared to what is observed for bacteriorhodopsin (BR). However, in the presence of Triton X-100 early proton release was observed in AR4 at neutral pH by us. Further, this temporal order for light-driven proton release and uptake for AR4 was found to be recovered after the removal of Triton X-100 by Biobeads. This phenomenon of detergent-induced alteration of the order of proton release and uptake has not yet been reported in any other retinal-containing membrane protein such as BR. Our findings indicate that the function of AR4 is influenced by its self-assembled state, and meanwhile imply some subtle protein-lipid interactions or protein-protein interactions in adjusting the proton pumping behavior of AR4.

Archaeal Proteins↗
PubMed2005

Clinical results of proton beam therapy for cancer of the esophagus.

PURPOSE: To present the results of proton beam therapy for patients with esophageal cancer. METHODS AND MATERIALS: This study reviewed 46 patients with esophageal cancer who were treated between 1985 and 1998 using proton beams with or without X-rays. All patients had locoregionally confined disease; all but one had squamous cell carcinoma. Of the 46 patients, 40 received combinations of X-rays (median, 48 Gy) and protons (median, 31.7 Gy) as a boost. The median total dose of combined X-ray and proton radiation for the 40 patients was 76.0 Gy (range, 69.1-87.4 Gy). The remaining 6 patients received only proton beam therapy (median, 82.0 Gy; range, 75-89.5 Gy). RESULTS: The 5-year actuarial survival rate for the 46 patients, patients with T1 (n = 23), and those with T2-T4 (n = 23) was 34%, 55%, and 13%, respectively. The 5-year disease-specific survival rate for the 46 patients, those with T1, and those with T2-T4 was 67%, 95%, and 33%, respectively. The 5-year local control rate for patients with T1 and T2-T4 lesions was 83% and 29%, respectively. The site of the first relapse was locoregional for 16 patients and distant organs for 2 patients. CONCLUSION: The results suggest that proton beam therapy is an effective treatment for patients with locally confined esophageal cancer. Additional studies are required to determine the optimal total dose, fractionation schedule, and best combinations of protons and conventional X-rays with or without chemotherapy.

Aged↗
PubMed2006

Accelerated partial breast irradiation using proton beams: Initial dosimetric experience.

PURPOSE: The unique dosimetric features of proton radiotherapy make it an attractive modality for normal tissue sparing. We present our initial experience with protons for three-dimensional, conformal, external-beam accelerated partial breast irradiation (3D-CPBI). METHODS AND MATERIALS: From March 2004 to June 2005, 25 patients with tumors < or =2 cm and negative axillary nodes were treated with proton 3D-CPBI. The prescribed dose was 32 Cobalt Gray Equivalents (CGE) in 4 CGE fractions given twice daily. One to three fields were used to provide adequate planning target volume (PTV) coverage and dose homogeneity. RESULTS: Excellent PTV coverage and dose homogeneity were obtained in all patients with one to three proton beams. The median PTV receiving 95% of the prescribed dose was 100%. Dose inhomogeneity exceeded 10% in only 1 patient (4%). The median volume of nontarget breast tissue receiving 50% of the prescribed dose was 23%. Median volumes of ipsilateral lung receiving 20 CGE, 10 CGE, and 5 CGE were 0%, 1%, and 2%, respectively. The contralateral lung and heart received essentially no radiation dose. Cost analysis suggests that proton 3D-CPBI is only modestly more expensive (25%) than traditional whole-breast irradiation (WBI). CONCLUSION: Proton 3D-CPBI is technically feasible, providing both excellent PTV coverage and normal tissue sparing. It markedly reduces the volume of nontarget breast tissue irradiated compared with photon-based 3D-CPBI, addressing a principle disadvantage of external-beam approaches to PBI. As proton therapy becomes more widely available, it may prove an attractive tool for 3D-CPBI.

Aged↗
PubMed2006

Dosimetric comparison of proton and photon three-dimensional, conformal, external beam accelerated partial breast irradiation techniques.

PURPOSE: To compare the dosimetry of proton and photon-electron three-dimensional, conformal, external beam accelerated partial breast irradiation (3D-CPBI). METHODS AND MATERIALS: Twenty-four patients with fully excised, Stage I breast cancer treated with adjuvant proton 3D-CPBI had treatment plans generated using the mixed-modality, photon-electron 3D-CPBI technique. To facilitate dosimetric comparisons, planning target volumes (PTVs; lumpectomy site plus 1.5-2.0 cm margin) and prescribed dose (32 Gy) were held constant. Plans were optimized for PTV coverage and normal tissue sparing. RESULTS: Proton and mixed-modality plans both provided acceptable PTV coverage with 95% of the PTV receiving 90% of the prescribed dose in all cases. Both techniques also provided excellent dose homogeneity with a dose maximum exceeding 110% of the prescribed dose in only one case. Proton 3D-CPBI reduced the volume of nontarget breast tissue receiving 50% of the prescribed dose by an average of 36%. Statistically significant reductions in the volume of total ipsilateral breast receiving 100%, 75%, 50%, and 25% of the prescribed dose were also observed. The use of protons resulted in small, but statistically significant, reductions in the radiation dose delivered to 5%, 10%, and 20% of ipsilateral and contralateral lung and heart. The nontarget breast tissue dosimetric advantages of proton 3D-CPBI were not dependent on tumor location, breast size, PTV size, or the ratio of PTV to breast volume. CONCLUSIONS: Compared to photon-electron 3D-CPBI, proton 3D-CPBI significantly reduces the volume of irradiated nontarget breast tissue. Both approaches to accelerated partial breast irradiation offer exceptional lung and heart sparing.

Aged↗
PubMed2006

Accelerated partial-breast irradiation using proton beams: initial clinical experience.

PURPOSE: We present our initial clinical experience with proton, three-dimensional, conformal, external beam, partial-breast irradiation (3D-CPBI). METHODS AND MATERIALS: Twenty patients with Stage I breast cancer were treated with proton 3D-CPBI in a Phase I/II clinical trial. Patients were followed at 3 to 4 weeks, 6 to 8 weeks, 6 months, and every 6 months thereafter for recurrent disease, cosmetic outcome, toxicity, and patient satisfaction. RESULTS: With a median follow-up of 12 months (range, 8-22 months), no recurrent disease has been detected. Global breast cosmesis was judged by physicians to be good or excellent in 89% and 100% of cases at 6 months and 12 months, respectively. Patients rated global breast cosmesis as good or excellent in 100% of cases at both 6 and 12 months. Proton 3D-CPBI produced significant acute skin toxicity with moderate to severe skin color changes in 79% of patients at 3 to 4 weeks and moderate to severe moist desquamation in 22% of patients at 6 to 8 weeks. Telangiectasia was noted in 3 patients. Three patients reported rib tenderness in the treated area, and one rib fracture was documented. At last follow-up, 95% of patients reported total satisfaction with proton 3D-CPBI. CONCLUSIONS: Based on our study results, proton 3D-CPBI offers good-to-excellent cosmetic outcomes in 89% to 100% of patients at 6-month and 12-month follow-up and nearly universal patient satisfaction. However, proton 3D-CPBI, as used in this study, does result in significant acute skin toxicity and may potentially be associated with late skin (telangiectasia) and rib toxicity. Because of the dosimetric advantages of proton 3D-CPBI, technique modifications are being explored to improve acute skin tolerance.

Aged↗
PubMed2006

Suppression of the back proton-transfer from Asp85 to the retinal Schiff base in bacteriorhodopsin: a theoretical analysis of structural elements.

The transfer of a proton from the retinal Schiff base to the nearby Asp85 protein group is an essential step in the directional proton-pumping by bacteriorhodopsin. To avoid the wasteful back reprotonation of the Schiff base from Asp85, the protein must ensure that, following Schiff base deprotonation, the energy barrier for back proton-transfer from Asp85 to the Schiff base is larger than that for proton-transfer from the Schiff base to Asp85. Here, three structural elements that may contribute to suppressing the back proton-transfer from Asp85 to the Schiff base are investigated: (i) retinal twisting; (ii) hydrogen-bonding distances in the active site; and (iii) the number and location of internal water molecules. The impact of the pattern of bond twisting on the retinal deprotonation energy is dissected by performing an extensive set of quantum-mechanical calculations. Structural rearrangements in the active site, such as changes of the Thr89:Asp85 distance and relocation of water molecules hydrogen-bonding to the Asp85 acceptor group, may participate in the mechanism which ensures that following the transfer of the Schiff base proton to Asp85 the protein proceeds with the subsequent photocycle steps, and not with back proton transfer from Asp85 to the Schiff base.

Animals↗
PubMed2000

Biophysical aspects of intra-protein proton transfer.

The passage of proton trough proteins is common to all membranal energy conserving enzymes. While the routes differ among the various proteins, the mechanism of proton propagation is based on the same chemical-physical principles. The proton progresses through a sequence of dissociation association steps where the protein and water molecules function as a solvent that lowers the energy penalty associated with the generation of ions in the protein. The propagation of the proton in the protein is a random walk, between the temporary proton binding sites that make the conducting path, that is biased by the intra-protein electrostatic potential. Kinetic measurements of proton transfer reactions, in the sub-ns up to micros time frame, allow to monitor the dynamics of the partial reactions of an overall proton transfer through a protein.

Arylsulfonates↗
PubMed2000

Proton pumping by cytochrome oxidase: progress, problems and postulates.

The current status of our knowledge about the mechanism of proton pumping by cytochrome oxidase is discussed. Significant progress has resulted from the study of site-directed mutants within the proton-conducting pathways of the bacterial oxidases. There appear to be two channels to facilitate proton translocation within the enzyme and they are important at different parts of the catalytic cycle. The use of hydrogen peroxide as an alternative substrate provides a very useful experimental tool to explore the enzymology of this system, and insights gained from this approach are described. Proton transfer is coupled to and appears to regulate the rate of electron transfer steps during turnover. It is proposed that the initial step in the reaction involves a proton transfer to the active site that is important to convert metal-ligated hydroxide to water, which can more rapidly dissociate from the metals and allow the reaction with dioxygen which, we propose, can bind the one-electron reduced heme-copper center. Coordinated movement of protons and electrons over both short and long distances within the enzyme appear to be important at different parts of the catalytic cycle. During the initial reduction of dioxygen, direct hydrogen transfer to form a tyrosyl radical at the active site seems likely. Subsequent steps can be effectively blocked by mutation of a residue at the surface of the protein, apparently preventing the entry of protons.

Animals↗
PubMed2002

Plasticity of proton pathways in haem-copper oxygen reductases.

Oxygen reductases are the final enzymes in the aerobic respiratory chains catalysing the reduction of dioxygen to water, with the concomitant translocation of protons through the bacterial cytoplasmatic or mitochondrial membranes. Most of these enzymes belong to the family of haem-copper oxygen reductases. Intraprotein proton-conducting pathways are needed for the chemical reaction and for the translocated protons. Based on sequence and structural analyses, and site-directed mutagenesis, two proton channels were established for the mitochondrial-like oxygen reductases. However, the amino acid residues forming these channels are not conserved among the family members. Most importantly, many oxygen reductases do not contain ionisable amino acid residues in the putative proton pathways nor in alternative positions. The diversity of channels in haem-copper oxygen reductases exemplifies the plasticity of proton pathways that occurred throughout evolution, and strongly suggests a substantial role for water as the main proton carrier.

Copper↗