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Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease. 相似文献
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Tobias M. Hedison Muralidharan Shanmugam Derren J. Heyes Ruth Edge Nigel S. Scrutton 《Angewandte Chemie (International ed. in English)》2020,59(33):13936-13940
Redox active metalloenzymes catalyse a range of biochemical processes essential for life. However, due to their complex reaction mechanisms, and often, their poor optical signals, detailed mechanistic understandings of them are limited. Here, we develop a cryoreduction approach coupled to electron paramagnetic resonance measurements to study electron transfer between the copper centers in the copper nitrite reductase (CuNiR) family of enzymes. Unlike alternative methods used to study electron transfer reactions, the cryoreduction approach presented here allows observation of the redox state of both metal centers, a direct read‐out of electron transfer, determines the presence of the substrate/product in the active site and shows the importance of protein motion in inter‐copper electron transfer catalyzed by CuNiRs. Cryoreduction‐EPR is broadly applicable for the study of electron transfer in other redox enzymes and paves the way to explore transient states in multiple redox‐center containing proteins (homo and hetero metal ions). 相似文献
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Shuyan Gong Mingze Sun Yiyang Lee Nigel Becknell Jiangwei Zhang Zhongqi Wang Liang Zhang Zhiqiang Niu 《Angewandte Chemie (International ed. in English)》2023,62(4):e202214516
Single crystal surfaces with highly coordinated sites very often hold high specific activities toward oxygen reduction reaction (ORR) and others. Transposing their high specific activity to practical high-surface-area electrocatalysts remains challenging. Here, ultrathin Pt(100) alloy surface is constructed via epitaxial growth. The surface shows 3.1–6.9 % compressive strain and bulk-like characteristics as demonstrated by site-probe reactions and different spectroscopies. Its ORR activity exceeds that of bulk Pt3Ni(100) and Pt(111) and presents a 19-fold increase in specific activity and a 13-fold increase in mass activity relative to commercial Pt/C. Moreover, the electrochemically active surface area (ECSA) is increased by 4-fold compared to traditional thin films (e.g. NSTF), which makes the catalyst more tolerant to voltage loss at high current densities under fuel cell operation. This work broadens the family of extended surface catalysts and highlights the knowledge-driven approach in the development of advanced electrocatalysts. 相似文献
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Frontispiece: Gd‐DTPA‐Dopamine‐Bisphytanyl Amphiphile: Synthesis,Characterisation and Relaxation Parameters of the Nanoassemblies and Their Potential as MRI Contrast Agents 下载免费PDF全文
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Adrián Serrano Mora Sean T. McBeath Clément A. Cid Michael R. Hoffmann Nigel J.D. Graham 《Current Opinion in Electrochemistry》2022
While diamond electrodes have been commonly used to generate ?OH to treat a variety of persistent water and wastewater micropollutants, mass transfer limitations and the non-selective, short-lived nature of the ?OH restrict the degradation to the solution at, or near, the electrode surface. However, diamond electrodes can generate oxidizing species that facilitate micropollutant degradation in the bulk water solution. These include persulfate, sulfate radicals, peroxodiphosphate, ferrate, permanganate, reactive chlorine species, hydrogen peroxide, and ozone, which have been reported during electrochemical treatment of water with diamond electrodes. Although still restricted to specialized applications, recent studies, summarized in this review, have proven the electrogeneration of these additional oxidant species to be effective. They have shown the adaptability and potential of diamond electrode-based water treatment to mitigate the presence of micropollutants in water. 相似文献
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Chelsea C. Buck Patrick B. Dennis Maneesh K. Gupta Marcus T. Grant Marquise G. Crosby Joseph M. Slocik Peter A. Mirau Kellie A. Becknell Kristen K. Comfort Rajesh R. Naik 《Macromolecular bioscience》2019,19(3)
The suckerin family of proteins, identified from the squid sucker ring teeth assembly, offers unique mechanical properties and potential advantages over other natural biomaterials. In this study, a small suckerin isoform, suckerin‐12, is used to create enzymatically crosslinked, macro‐scale hydrogels. Upon exposure to specific salt conditions, suckerin‐12 hydrogels contracted into a condensed state where mechanical properties are found to be modulated by the salt anion present. The rate of contraction is found to correlate well with the kosmotropic arm of the Hofmeister anion series. However, the observed changes in hydrogel mechanical properties are better explained by the ability of the salt to neutralize charges in suckerin‐12 by deprotonization or charge screening. Thus, by altering the anions in the condensing salt solution, it is possible to tune the mechanical properties of suckerin‐12 hydrogels. The potential for suckerins to add new properties to materials based on naturally‐derived proteins is highlighted. 相似文献
8.
Nigel M. Groome Elghareeb E. Elboray Dr. Martyn W. Inman Prof. H. Ali Dondas Dr. Roger M. Phillips Colin Kilner Prof. Ronald Grigg 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(6):2180-2184
Naturally occurring indole‐3‐carbinol and 3,3‐diindolylmethane show bioactivity in a number of disparate disease areas, including cancer, prompting substantial synthetic analogue activity. We describe a new approach to highly functionalised derivatives that starts from allene gas and proceeds via the combination of a three‐component Pd0‐catalysed cascade with a one‐pot, three‐component carbophilic PtII cascade linked to a stereoselective acid‐catalysed Mannich–Michael reaction that generates complex cyclopropyl diindolylmethanes which show selective activity against prostate cancer cell lines. 相似文献
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