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  • 1
    Language: English
    In: The journal of physical chemistry. A, 18 December 2008, Vol.112(50), pp.12911-8
    Description: To examine how azole inhibitors interact with the heme active site of the cytochrome P450 enzymes, we have performed a series of density functional theory studies on azole binding. These are the first density functional studies on azole interactions with a heme center and give fundamental insight into how azoles inhibit the catalytic function of P450 enzymes. Since azoles come in many varieties, we tested three typical azole motifs representing a broad range of azole and azole-type inhibitors: methylimidazolate, methyltriazolate, and pyridine. These structural motifs represent typical azoles, such as econazole, fluconazole, and metyrapone. The calculations show that azole binding is a stepwise mechanism whereby first the water molecule from the resting state of P450 is released from the sixth binding site of the heme to create a pentacoordinated active site followed by coordination of the azole nitrogen to the heme iron. This process leads to the breaking of a hydrogen bond between the resting state water molecule and the approaching inhibitor molecule. Although, formally, the water molecule is released in the first step of the reaction mechanism and a pentacoordinated heme is created, this does not lead to an observed spin state crossing. Thus, we show that release of a water molecule from the resting state of P450 enzymes to create a pentacoordinated heme will lead to a doublet to quartet spin state crossing at an Fe-OH(2) distance of approximately 3.0 A, while the azole substitution process takes place at shorter distances. Azoles bind heme with significantly stronger binding energies than a water molecule, so that these inhibitors block the catalytic cycle of the enzyme and prevent oxygen binding and the catalysis of substrate oxidation. Perturbations within the active site (e.g., a polarized environment) have little effect on the relative energies of azole binding. Studies with an extra hydrogen-bonded ethanol molecule in the model, mimicking the active site of the CYP121 P450, show that the resting state and azole binding structures are close in energy, which may lead to chemical equilibrium between the two structures, as indeed observed with recent protein structural studies that have demonstrated two distinct azole binding mechanisms to P450 heme.
    Keywords: Cytochrome P-450 Enzyme Inhibitors ; Azoles -- Pharmacology ; Cytochrome P-450 Enzyme System -- Chemistry ; Enzyme Inhibitors -- Pharmacology
    ISSN: 10895639
    E-ISSN: 1520-5215
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  • 2
    In: Global Change Biology, October 2015, Vol.21(10), pp.3836-3845
    Description: Organic carbon () sequestration in degraded semi‐arid environments by improved soil management is assumed to contribute substantially to climate change mitigation. However, information about the soil organic carbon () sequestration potential in steppe soils and their current saturation status remains unknown. In this study, we estimated the storage capacity of semi‐arid grassland soils on the basis of remote, natural steppe fragments in northern China. Based on the maximum saturation of silt and clay particles 〈20 μm, sequestration potentials of degraded steppe soils (grazing land, arable land, eroded areas) were estimated. The analysis of natural grassland soils revealed a strong linear regression between the proportion of the fine fraction and its content, confirming the importance of silt and clay particles for stabilization in steppe soils. This relationship was similar to derived regressions in temperate and tropical soils but on a lower level, probably due to a lower C input and different clay mineralogy. In relation to the estimated storage capacity, degraded steppe soils showed a high saturation of 78–85% despite massive losses due to unsustainable land use. As a result, the potential of degraded grassland soils to sequester additional was generally low. This can be related to a relatively high contribution of labile , which is preferentially lost in the course of soil degradation. Moreover, wind erosion leads to substantial loss of silt and clay particles and consequently results in a direct loss of the ability to stabilize additional . Our findings indicate that the loss in semi‐arid environments induced by intensive land use is largely irreversible. Observed increases after improved land management mainly result in an accumulation of labile prone to land use/climate changes and therefore cannot be regarded as contribution to long‐term sequestration.
    Keywords: Climate Change ; Fine Fraction ; Soil Organic Carbon ; Soil Texture ; Steppe Soils
    ISSN: 1354-1013
    E-ISSN: 1365-2486
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  • 3
    Language: English
    In: Biochemistry, 01 May 2007, Vol.46(17), pp.5018-29
    Description: Multiple solution-state techniques have been employed in investigating the nature and control of electron transfer in the context of the proposed "domain shuffle hypothesis" for intraprotein electron transfer inferred from the crystal structure of the nitric oxide synthase reductase domain. NADPH analogues and fragments have been used to map those regions of this substrate that are important in eliciting a conformational change, observed in both the fluorescence emission of the flavin cofactors of the enzyme and the EPR spectra of the FMN flavosemiquinone state. EPR and UV-visible potentiometric methods have demonstrated a substantial calmodulin-dependent perturbation in the midpoint reduction potentials of the redox couples of both flavin cofactors, in contrast to a previous report [Noble, M. A., et al. (1999) Biochemistry 38, 16413-16418]. These studies support a model in which FMN domain mobility, triggered by Ca2+-calmodulin binding and antagonized by substrate binding, facilitates electron transfer in nitric oxide synthase through conformational change and effects a major change in the midpoint reduction potentials of the flavin redox couples. These results are discussed in light of the recent crystal structure of the NADPH-locked reductase domain.
    Keywords: Thermodynamics ; Nitric Oxide Synthase Type I -- Chemistry
    ISSN: 0006-2960
    E-ISSN: 15204995
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  • 4
    In: FEBS Journal, September 2008, Vol.275(18), pp.4540-4557
    Description: This study on human cytochrome P450 reductase (CPR) presents a comprehensive analysis of the thermodynamic and kinetic effects of pH and solvent on two‐ and four‐electron reduction in this diflavin enzyme. pH‐dependent redox potentiometry revealed that the thermodynamic equilibrium between various two‐electron reduced enzyme species (FMNH,FADH; FMN,FADH; FMNH,FAD) is independent of pH. No shift from the blue, neutral di‐semiquinone (FMNH,FADH) towards the red, anionic species is observed upon increasing the pH from 6.5 to 8.5. Spectrophotometric analysis of events following the mixing of oxidized CPR and NADPH (1 to 1) in a stopped‐flow instrument demonstrates that the establishment of this thermodynamic equilibrium becomes a very slow process at elevated pH, indicative of a pH‐gating mechanism. The final level of blue di‐semiquinone formation is found to be pH independent. Stopped‐flow experiments using excess NADPH over CPR provide evidence that both pH and solvent significantly influence the kinetic exposure of the blue di‐semiquinone intermediate, yet the observed rate constants are essentially pH independent. Thus, the kinetic pH‐gating mechanism under stoichiometric conditions is of no significant kinetic relevance for four‐electron reduction, but rather modulates the observed semiquinone absorbance at 600 nm in a pH‐dependent manner. The use of proton inventory experiments and primary kinetic isotope effects are described as kinetic tools to disentangle the intricate pH‐dependent kinetic mechanism in CPR. Our analysis of the pH and isotope dependence in human CPR reveals previously hidden complexity in the mechanism of electron transfer in this complex flavoprotein.
    Keywords: Electron Transfer ; Ph Dependence ; Redox Potentiometry ; Solvent Kinetic Isotope Effect ; Stopped‐Flow
    ISSN: 1742-464X
    E-ISSN: 1742-4658
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  • 5
    Language: English
    In: Journal of Neuroimmunology, 1985, Vol.8, pp.29-41
    Description: An extensive analysis of the relationship between immunological parameters and clinical responses and biochemical loss of muscle acetylcholine receptors (AChR) was performed in murine experimental autoimmune myasthenia gravis. The onset of clinical muscle weakness correlated strongly with the onset of significant muscle AChR loss. Mice with clinical muscle weakness had greater amount of muscle AChR loss. There was no correlation between the concentration of anti-AChR antibodies and the presence of clinical muscle weakness or amount of muscle AChR loss. However, the kinetics of autoantibody response correlated well with that of muscle AChR loss.
    Keywords: Anti-Achr Antibodies ; Murine Experimental Autoimmune Myasthenia Gravis ; Muscle Acetylcholine Receptors (Achr) ; Medicine ; Anatomy & Physiology
    ISSN: 0165-5728
    E-ISSN: 1872-8421
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  • 6
    Language: English
    In: Forestry, 2004, Vol.77(4), pp.335-347
    Description: We report a method using variation in the chloroplast genome (cpDNA) to test whether oak stands of unknown provenance are of native and/or local origin. As an example, a sample of test oaks, of mostly unknown status in relation to nativeness and localness, were surveyed for cpDNA type. The sample comprised 126 selected trees, derived from 16 British seed stands, and 75 trees, selected for their superior phenotype (201 tree samples in total). To establish whether these two test groups are native and local, their cpDNA type was compared with that of material from known autochthonous origin (results of a previous study which examined variation in 1076 trees from 224 populations distributed across Great Britain). In the previous survey of autochthonous material, four cpDNA types were identified as native; thus if a test sample possessed a new haplotype then it could be classed as non-native. Every one of the 201 test samples possessed one of the four cpDNA types found within the autochthonous sample. Therefore none could be proven to be introduced and, on this basis, was considered likely to be native. The previous study of autochthonous material also found that cpDNA variation was highly structured geographically and, therefore, if the cpDNA type of the test sample did not match that of neighbouring autochthonous trees then it could be considered to be non-local. A high proportion of the seed stand group (44.2 per cent) and the phenotypically superior trees (58.7 per cent) possessed a cpDNA haplotype which matched that of the neighbouring autochthonous trees and, therefore, can be considered as local, or at least cannot be proven to be introduced. The remainder of the test sample could be divided into those which did not grow in an area of overall dominance (18.7 per cent of seed stand trees and 28 per cent of phenotypically superior) and those which failed to match the neighbouring autochthonous haplotype (37.1 per cent and 13.3 per cent, respectively). Most of the non-matching test samples were located within 50 km of an area dominated by a matching autochthonous haplotype (96.0 per cent and 93.5 per cent, respectively), and potentially indicates only local transfer. Whilst such genetic fingerprinting tests have proven useful for assessing the origin of stands of unknown provenance, there are potential limitations to using a marker from the chloroplast genome (mostly adaptively neutral) for classifying seed material into categories which have adaptive implications. These limitations are discussed, particularly within the context of selecting adaptively superior material for restocking native forests.
    Keywords: Forestry;
    ISSN: 0015-752X
    E-ISSN: 1464-3626
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  • 7
    In: Nature, 2016, Vol.539(7630), p.593
    Description: The universal Per-ARNT-Sim (PAS) domain functions as a signal transduction module involved in sensing diverse stimuli such as small molecules, light, redox state and gases. The highly evolvable PAS scaffold can bind a broad range of ligands, including haem, flavins and metal ions. However, although these ligands can support catalytic activity, to our knowledge no enzymatic PAS domain has been found. Here we report characterization of the first PAS enzyme: a haem-dependent oxidative N-demethylase. Unrelated to other amine oxidases, this enzyme contains haem, flavin mononucleotide, 2Fe-2S and tetrahydrofolic acid cofactors, and specifically catalyses the NADPH-dependent oxidation of dimethylamine. The structure of the α subunit reveals that it is a haem-binding PAS domain, similar in structure to PAS gas sensors. The dimethylamine substrate forms part of a highly polarized oxygen-binding site, and directly assists oxygen activation by acting as both an electron and proton donor. Our data reveal that the ubiquitous PAS domain can make the transition from sensor to enzyme, suggesting that the PAS scaffold can support the development of artificial enzymes.
    Keywords: Oxidoreductases, N-Demethylating -- Chemistry ; Pseudomonas Mendocina -- Enzymology;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 8
    Language: English
    In: Aquaculture, 20 April 2017, Vol.473, pp.251-258
    Description: Bacteriophage therapy has demonstrated promising results towards the control of bacterial infections within the aquaculture industry as an alternative therapy to antibiotics. This current research describes the efficacy of bacteriophage therapy in controlling vibriosis within abalone ( ). Two bacteriophages were isolated and used in assays to determine the effect of each specific phage on the growth of specific isolates. To demonstrate efficacy, an bioassay was performed using abalone ( . ) at a water temperature of 24 °C. Characterisation of the two isolated phages revealed they were from the family, . The phages had different antimicrobial abilities towards different isolates in the assays and the bioassay demonstrated improved survival of abalone treated with bacteriophage. The results of the bioassay showed that the negative control and phage control were statistically identical, with 100% survival, but they were different from the positive bacterial control, with a 0% survival. The bacteria + phage treated group showed increased accumulative survival of 70% compared to the positive control. This is the first study to demonstrate the efficacy of bacteriophage therapy treatment for abalone. The study demonstrates that if abalones are treated with bacteriophage shortly after infection, the accumulative survival could be significantly increased.
    Keywords: Bacteriophage ; Therapy ; Abalone ; Health ; Aquaculture ; Disease ; Agriculture
    ISSN: 0044-8486
    E-ISSN: 1873-5622
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  • 9
    Language: English
    In: Developmental Cell, 12 October 2015, Vol.35(1), pp.131-142
    Description: Dynamic maintenance of cell polarity is essential for development and physiology. Here we combine experiments and modeling to elucidate mechanisms that maintain cortical polarity in the zygote. We show that polarity is dynamically stabilized by two coupled cross-inhibitory feedback loops: one involves the oligomeric scaffold PAR-3 and the kinase PAR-1, and the other involves CDC-42 and its putative GAP CHIN-1. PAR-3 and CDC-42 are both required locally to recruit PAR-6/PKC-3, which inhibits PAR-1 (shown previously) and inhibits local growth/accumulation of CHIN-1 clusters. Conversely, PAR-1 inhibits local accumulation of PAR-3 oligomers, while CHIN-1 inhibits CDC-42 (shown previously), such that either PAR-1 or CHIN-1 can prevent recruitment of PAR-6/PKC-3, but loss of both causes complete loss of polarity. Ultrasensitive dependence of CHIN-1 cluster growth on PAR-6/PKC-3 endows this core circuit with bistable dynamics, while transport of CHIN-1 clusters by cortical flow can stabilize the AP boundary against diffusive spread of PAR-6/PKC-3. Sailer et al. show that in the zygote, polarity is maintained by two redundant cross-inhibitory loops, both involving dynamically clustered polarity proteins. Threshold dependence of cluster growth on opposing kinases stabilizes complementary cortical domains, while cortical transport of clustered proteins can stabilize boundary position against diffusive drift.
    Keywords: Biology
    ISSN: 1534-5807
    E-ISSN: 1878-1551
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  • 10
    Language: English
    In: Current Topics in Medicinal Chemistry, 2013, Vol.13(18), p.2218-2232
    Description: There is a major controversy in cytochrome P450 chemistry regarding the nature of the active oxidant responsible for substrate monoxygenation. Part of this controversy originates from the fact that the later stages in the catalytic cycle of P450 enzymes proceed so fast that little experimental evidence is available. Early studies suggested an iron(IV)- oxo heme cation radical ([heme(〈sup〉+.〈/sup〉)-Fe〈sup〉IV〈/sup〉=O] or Compound I) as the active species able to abstract a hydrogen atom from a substrate and rebind the hydroxyl group to form an alcohol product. Such simplistic early models involving a single active species have subsequently been invalidated by several experimental studies which clearly indicates that there must be at least two active species of some description. Based on these and other data, a two-oxidant hypothesis was put forward where Compound I and its precursor in the catalytic cycle ([heme-Fe〈sup〉III〈/sup〉-OOH]- or Compound 0) are competitive oxidants. Density functional theory studies, however, suggest an alternative hypothesis involving a two-state-reactivity scenario where Compound I has two close-lying spin states that react differently with substrates and masquerade as two distinct oxidants. These theoretical studies show that the two spin states of Compound I react with substrates via aliphatic and aromatic C-H hydroxylation, C=C epoxidation and sulfoxidation reactions, and explain experimentally observed product distributions and kinetic isotope effects. This review will give an overview of recent studies on the two-oxidant versus two-state-reactivity hypotheses and how theory contributes to the understanding of enzymatic reaction processes.
    Keywords: P450 Enzymes Compound I Compound 0 Density Functional Theory Enzyme Modeling Enzyme Function Iron-Oxo Chemistry Oxygen.
    ISSN: 1568-0266
    E-ISSN: 1873-5294
    E-ISSN: 18734294
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