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51.
Hope Adamson Alexandr N. Simonov Michelina Kierzek Richard A. Rothery Joel H. Weiner Alan M. Bond Alison Parkin 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(47):14506-14511
A long-standing contradiction in the field of mononuclear Mo enzyme research is that small-molecule chemistry on active-site mimic compounds predicts ligand participation in the electron transfer reactions, but biochemical measurements only suggest metal-centered catalytic electron transfer. With the simultaneous measurement of substrate turnover and reversible electron transfer that is provided by Fourier-transformed alternating-current voltammetry, we show that Escherichia coli YedY is a mononuclear Mo enzyme that reconciles this conflict. In YedY, addition of three protons and three electrons to the well-characterized “as-isolated” Mo(V) oxidation state is needed to initiate the catalytic reduction of either dimethyl sulfoxide or trimethylamine N-oxide. Based on comparison with earlier studies and our UV-vis redox titration data, we assign the reversible one-proton and one-electron reduction process centered around +174 mV vs. standard hydrogen electrode at pH 7 to a Mo(V)-to-Mo(IV) conversion but ascribe the two-proton and two-electron transition occurring at negative potential to the organic pyranopterin ligand system. We predict that a dihydro-to-tetrahydro transition is needed to generate the catalytically active state of the enzyme. This is a previously unidentified mechanism, suggested by the structural simplicity of YedY, a protein in which Mo is the only metal site.Most living species require a Mo enzyme (1), and apart from nitrogenase, all of these Mo-containing proteins are part of the large family of “mononuclear Mo” enzymes. The general ability of mononuclear Mo enzymes to catalyze two-electron oxygen atom transfer reactions has been attributed to the Mo(IV)/Mo(V)/Mo(VI) oxidation state cycling of the active site, and this mechanism is a common part of undergraduate syllabuses (1, 2). Escherichia coli YedY is a mononuclear Mo enzyme (3), and based on sequence homology, the majority of sequenced Gram-negative bacterial genomes encode a YedY-like protein (3–5). Uniquely for a mononuclear Mo enzyme, it has not been possible to form the YedY Mo(VI) state in experiments using ferricyanide as an oxidizing agent, and an unusually positive reduction potential for the Mo(V/IV) transition [+132 mV vs. standard hydrogen electrode (SHE) at pH 7] was determined from EPR experiments (6). Although the physiological substrate of YedY is unknown, a possible role in the reduction of reactive nitrogen species is suggested by experiments on the pathogen Campylobacter jejuni, where deletion of the Cj0379 YedY homolog generated a mutant that is deficient in chicken colonization and has a nitrosative stress phenotype (4). YedY catalysis can be assayed by measuring the two-electron reduction of either dimethyl sulfoxide (DMSO) or trimethylamine N-oxide (TMAO) (3), but the inaccessibility of the YedY Mo(VI) means the enzyme mechanism does not proceed via the common two-electron Mo-redox cycle. In small-molecule analogs of mononuclear Mo enzymes, the pterin ligands are described as “noninnocent,” meaning that the redox processes could be ligand or metal based (7). This study explores the possibility that ligand-based redox chemistry plays a role in YedY catalysis.YedY has been structurally characterized via both X-ray crystallography and X-ray absorption spectroscopy (XAS) (3, 8, 9). In most mononuclear Mo enzymes, heme groups and iron sulfur clusters are found within the same protein as the Mo center, but the only metal site in YedY is Mo, making this enzyme a helpfully simple system for studying redox chemistry (Fig. 1) (1, 3). Within the active site, the X-ray structure was interpreted to show Mo(V) in a square pyramidal environment (3), identical to other members of the “sulfite oxidase” family of mononuclear Mo enzymes. In contrast, XAS has suggested a pseudooctahedral Mo center (8, 9) with an additional O (from Glu104) or N (from Asn45) axial ligand coordinating trans to the apical oxo group (Fig. 1) (8). The equatorial ligation is provided by one oxygen-containing ligand and three sulfur donor atoms, one provided by cysteine (Cys102) and two from the pyranopterin cofactor, which binds to the Mo in a bidentate fashion via the enedithiolate side chain (3).Open in a separate windowFig. 1.Structure of Escherichia coli YedY. (A and B) The protein structure, PDB ID code 1XDQ (3). (C) The active site in the as-isolated Mo(V) state containing the dihydro form of pyranopterin.A 2012 computational study provided evidence that two different oxidation states can be accessed by protein-bound pyranopterin ligands (10). Conformational analysis and electronic structure calculations were used to assign redox states to the pyranopterin ligands in all known mononuclear Mo enzyme structures (10). It was concluded that, although enzymes from the sulfite oxidase family (such as YedY) contain pyranopterin ligands in the “dihydro” form, the xanthine dehydrogenase family of enzymes contain the two-proton, two-electron more reduced “tetrahydro” form of the pyranopterin (10).Traditionally, redox potential measurements of enzymes have required substrate-free conditions to either permit a solution equilibrium to be established (spectroscopic redox titrations) or to prevent catalytic signals from masking the noncatalytic response (film electrochemistry). Fourier-transformed alternating-current voltammetry (FTacV) is a technique that offers the ability to measure catalytic chemical redox reactions and reversible electron transfer processes in a single experiment (11, 12). In the FTacV measurement, a large-amplitude sine wave of frequency f is superimposed on a linear voltage–time sweep (11, 13–15) and the resulting current–time response is measured and then Fourier transformed (FT) into the frequency domain to give a power spectrum of harmonic contributions at frequencies f, 2f, 3f, etc. Band selection of the individual harmonics followed by inverse FT resolves the data back into the time domain. The higher harmonic components only arise from fast, reversible redox reactions, devoid of catalysis and baseline contributions, but the aperiodic (dc) component (f = 0) gives the same catalytic information as a traditional dc cyclic voltammetry (dcV) experiment, and can therefore show catalytic turnover (13, 14, 16).In this study, we both discover previously unidentified mononuclear Mo enzyme redox chemistry as well as demonstrate the significant advantages of using FTacV to probe the mechanism of a redox active enzyme. 相似文献
52.
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54.
Bernhard F. Gibbs Isabel Gon?alves Silva Alexandr Prokhorov Maryam Abooali Inna M. Yasinska Maxwell A. Casely-Hayford Steffen M. Berger Elizaveta Fasler-Kan Vadim V. Sumbayev 《Oncotarget》2015,6(30):28678-28692
Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells. 相似文献
55.
OBJECTIVE: To study the effectiveness and safety of as-needed treatment of formoterol compared with the short-acting alternative terbutaline. METHODS: Two double-blind, 12-month, parallel-group, non-inferiority trials comparing as-needed use of formoterol (Oxis) 4.5 microg and terbutaline (Bricanyl) 0.5 mg via dry-powder inhaler (Turbuhaler), one in 675 patients with intermittent and one in 455 patients with mild persistent asthma, overall 6-87 years of age. Peak expiratory flow (PEF), symptoms, rescue medication use, exacerbations, airway responsiveness (metacholine challenge; subgroup of 127 patients), systemic effects (high single-dose test; subgroup of 87 patients), and safety (adverse events) were assessed. RESULTS: Formoterol 4.5 microg was as effective as terbutaline 0.5 mg with regard to morning PEF (non-inferiority; lower 95% confidence interval limit above -10 L/min). Metacholine sensitivity, exacerbation rates or use of rescue medication did not differ between treatments. Formoterol 54 microg was shown to give less systemic effects than terbutaline 6 mg. Both treatments were safe and well tolerated. CONCLUSIONS: Formoterol 4.5 microg used as needed was at least as effective and safe as terbutaline 0.5 mg used as needed in intermittent and mild persistent asthma, and was associated with less systemic effects when administered as high single doses. 相似文献
56.
Vera Chernonosova Alexandr Gostev Ivan Murashov Boris Chelobanov Andrey Karpenko Pavel Laktionov 《Materials》2021,14(13)
We examined the physicochemical properties and the biocompatibility and hemocompatibility of electrospun 3D matrices produced using polyurethane Pellethane 2363-80A (Pel-80A) blends Pel-80A with gelatin or/and bivalirudin. Two layers of vascular grafts of 1.8 mm in diameter were manufactured and studied for hemocompatibility ex vivo and functioning in the infrarenal position of Wistar rat abdominal aorta in vivo (n = 18). Expanded polytetrafluoroethylene (ePTFE) vascular grafts of similar diameter were implanted as a control (n = 18). Scaffolds produced from Pel-80A with Gel showed high stiffness with a long proportional limit and limited influence of wetting on mechanical characteristics. The electrospun matrices with gelatin have moderate capacity to support cell adhesion and proliferation (~30–47%), whereas vascular grafts with bivalirudin in the inner layer have good hemocompatibility ex vivo. The introduction of bivalirudin into grafts inhibited platelet adhesion and does not lead to a change hemolysis and D-dimers concentration. Study in vivo indicates the advantages of Pel-80A grafts over ePTFE in terms of graft occlusion, calcification level, and blood velocity after 6 months of implantation. The thickness of neointima in Pel-80A–based grafts stabilizes after three months (41.84 ± 20.21 µm) and does not increase until six months, demonstrating potential for long-term functioning without stenosis and as a suitable candidate for subsequent preclinical studies in large animals. 相似文献
57.
58.
Zoia R. Korobova Elena V. Zueva Natalia A. Arsentieva Oleg K. Batsunov Natalia E. Liubimova Irina V. Khamitova Raisa N. Kuznetsova Artem A. Rubinstein Tikhon V. Savin Oksana V. Stanevich Alexandr N. Kulikov Dmitry E. Pevtsov Areg A. Totolian 《Viruses》2022,14(5)
IgG is the most prominent marker of post-COVID-19 immunity. Not only does this subtype mark the late stages of infection, but it also stays in the body for a timespan of at least 6 months. However, different IgG subclasses have different properties, and their roles in specific anti-COVID-19 responses have yet to be determined. We assessed the concentrations of IgG1, IgG2, IgG3, and IgG4 against different SARS-CoV-2 antigens (N protein, S protein RBD) using a specifically designed method and samples from 348 COVID-19 patients. We noted a statistically significant association between severity of COVID-19 infection and IgG concentrations (both total and subclasses). When assessing anti-N protein and anti-RBD IgG subclasses, we noted the importance of IgG3 as a subclass. Since it is often associated with early antiviral response, we presumed that the IgG3 subclass is the first high-affinity IgG antibody to be produced during COVID-19 infection. 相似文献
59.
Vladimir G. Bespalov Ivan K. Alvovsky Grigory V. Tochilnikov Alexandr N. Stukov Ekaterina A. Vyshinskaya Alexandr L. Semenov 《International journal of hyperthermia》2018,34(5):545-550
Objectives: The choice of an optimal administration route for intraperitoneal (IP) chemotherapy and a suitable chemotherapeutic regime in the treatment of ovarian cancer remains a controversy. We investigated survival outcomes according to catheter intraperitoneal chemotherapy (CIPC), normothermic and hyperthermic chemoperfusion (NIPEC and HIPEC) with cytostatic drugs dioxadet and cisplatin in rats with transplantable ascitic ovarian cancer.Methods: Ascitic liquid containing 1?×?107 tumour cells was inoculated to female Wistar rats and 48?hours after rats received dioxadet and cisplatin at the maximum tolerated doses. Dioxadet at doses 1.5, 30 and 15?mg/kg and cisplatin at doses 4, 40 and 20?mg/kg body weight were administered for CIPC, NIPEC and HIPEC, respectively. Rats in the control groups received physiological saline and CIPC with physiological saline was regarded as the untreated control. The antitumor activity of the drugs was evaluated as an increase in average life expectancy (ALE). Analysis of the data was based primarily on Bayesian statistics and included Kaplan–Meier method, log-rank test and hazard ratio (HR) estimation.Results: Compared to the untreated control CIPC, NIPEC and HIPEC with dioxadet significantly increased ALE by 101316, 61524 and 1.71735 days, whereas with cisplatin by 61013, 122437 and –13523 days, respectively.Conclusions: Dioxadet and cisplatin show similar efficacy in the CIPC route. Compared with CIPC IP chemotherapy by chemoperfusions is more effective for both the drugs. Dioxadet in HIPEC showed highest survival benefit whereas largest effect during NIPEC is achieved with cisplatin. 相似文献
60.
M Chvála 《Angewandte Parasitologie》1979,20(1):38-45
The daily activity of Tabanidae (Diptera) was studied in the submountain region of the East Caucasus, district Ismailly, NE Azerbaijan SSR at an altitude 900--1000 m. Tabanidae were collected by the unbaited canopy trap on 8 and 12 July 1976. Females were active from 9 a. m. to 7 p. m., the diurnal biting activity is characterized by a one peak curve with a conspicuous peak of activity between 4 p. m. and 6 p. m. It is suggested that the temperature, relative humidity and the thermic mountain wind are the decisive factors influencing the late afternoon peak of activity. Mating activity of Tabanus unifasciatus at sunrise and of Philipomyia aprica at sunset were observed. 相似文献