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121.
The role of copper(II) and zinc(II) in the degradation of human and murine IAPP by insulin‐degrading enzyme 下载免费PDF全文
Amylin or islet amyloid polypeptide (IAPP) is a 37‐residue peptide hormone secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. IAPP aggregates are strongly associated with β‐cell degeneration in type 2 diabetes, as demonstrated by the fact that more than 95% of patients exhibit IAPP amyloid upon autopsy. Recently, it has been reported that metal ions such as copper(II) and zinc(II) are implicated in the aggregation of IAPP as well as able to modulate the proteolytic activity of IAPP degrading enzymes. For this reason, in this work, the role of the latter metal ions in the degradation of IAPP by insulin‐degrading enzyme (IDE) has been investigated by a chromatographic and mass spectrometric combined method. The latter experimental approach allowed not only to assess the overall metal ion inhibition of the human and murine IAPP degradation by IDE but also to have information on copper‐ and zinc‐induced changes in IAPP aggregation. In addition, IDE cleavage site preferences in the presence of metal ions are rationalized as metal ion‐induced changes in substrate accessibility. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
122.
Enzymatic Conversion of Flavonoids using Bacterial Chalcone Isomerase and Enoate Reductase 下载免费PDF全文
Dipl.‐Biol. Mechthild Gall Dipl.‐Biochem. Maren Thomsen Dipl.‐Biochem. Christin Peters Dr. Ioannis V. Pavlidis M. Sc. Patrick Jonczyk M. Sc. Philipp P. Grünert Dr. Sascha Beutel Prof. Dr. Thomas Scheper Egon Gross Dr. Michael Backes Dr. Torsten Geißler Dr. Jakob P. Ley Dr. Jens‐Michael Hilmer Dr. Gerhard Krammer Dr. Gottfried J. Palm Prof. Dr. Winfried Hinrichs Prof. Dr. Uwe T. Bornscheuer 《Angewandte Chemie (International ed. in English)》2014,53(5):1439-1442
Flavonoids are a large group of plant secondary metabolites with a variety of biological properties and are therefore of interest to many scientists, as they can lead to industrially interesting intermediates. The anaerobic gut bacterium Eubacterium ramulus can catabolize flavonoids, but until now, the pathway has not been experimentally confirmed. In the present work, a chalcone isomerase (CHI) and an enoate reductase (ERED) could be identified through whole genome sequencing and gene motif search. These two enzymes were successfully cloned and expressed in Escherichia coli in their active form, even under aerobic conditions. The catabolic pathway of E. ramulus was confirmed by biotransformations of flavanones into dihydrochalcones. The engineered E. coli strain that expresses both enzymes was used for the conversion of several flavanones, underlining the applicability of this biocatalytic cascade reaction. 相似文献
123.
Structure‐Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry 下载免费PDF全文
Milon Mondal Nedyalka Radeva Dr. Helene Köster Dr. Ahyoung Park Dr. Constantinos Potamitis Dr. Maria Zervou Prof. Dr. Gerhard Klebe Dr. Anna K. H. Hirsch 《Angewandte Chemie (International ed. in English)》2014,53(12):3259-3263
Structure‐based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein‐bound library member(s) by saturation‐transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization. 相似文献
124.
Mechanistic Insights into RNA Transphosphorylation from Kinetic Isotope Effects and Linear Free Energy Relationships of Model Reactions 下载免费PDF全文
Haoyuan Chen Dr. Timothy J. Giese Dr. Ming Huang Prof. Dr. Kin‐Yiu Wong Prof. Dr. Michael E. Harris Prof. Dr. Darrin M. York 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(44):14336-14343
Phosphoryl transfer reactions are ubiquitous in biology and the understanding of the mechanisms whereby these reactions are catalyzed by protein and RNA enzymes is central to reveal design principles for new therapeutics. Two of the most powerful experimental probes of chemical mechanism involve the analysis of linear free energy relations (LFERs) and the measurement of kinetic isotope effects (KIEs). These experimental data report directly on differences in bonding between the ground state and the rate‐controlling transition state, which is the most critical point along the reaction free energy pathway. However, interpretation of LFER and KIE data in terms of transition‐state structure and bonding optimally requires the use of theoretical models. In this work, we apply density‐functional calculations to determine KIEs for a series of phosphoryl transfer reactions of direct relevance to the 2′‐O‐transphosphorylation that leads to cleavage of the phosphodiester backbone of RNA. We first examine a well‐studied series of phosphate and phosphorothioate mono‐, di‐ and triesters that are useful as mechanistic probes and for which KIEs have been measured. Close agreement is demonstrated between the calculated and measured KIEs, establishing the reliability of our quantum model calculations. Next, we examine a series of RNA transesterification model reactions with a wide range of leaving groups in order to provide a direct connection between observed Brønsted coefficients and KIEs with the structure and bonding in the transition state. These relations can be used for prediction or to aid in the interpretation of experimental data for similar non‐enzymatic and enzymatic reactions. Finally, we apply these relations to RNA phosphoryl transfer catalyzed by ribonuclease A, and demonstrate the reaction coordinate–KIE correlation is reasonably preserved. A prediction of the secondary deuterium KIE in this reaction is also provided. These results demonstrate the utility of building up knowledge of mechanism through the systematic study of model systems to provide insight into more complex biological systems such as phosphoryl transfer enzymes and ribozymes. 相似文献
125.
126.
Xiaonan Duan Dr. Stéphane C. Corgié Prof. Daniel J. Aneshansley Prof. Peng Wang Prof. Larry P. Walker Prof. Emmanuel P. Giannelis 《Chemphyschem》2014,15(5):974-980
We report a new family of hierarchical hybrid catalysts comprised of horseradish peroxidase (HRP)–magnetic nanoparticles for advanced oxidation processes and demonstrate their utility in the removal of phenol from water. The immobilized HRP catalyzes the oxidation of phenols in the presence of H2O2, producing free radicals. The phenoxy radicals react with each other in a non‐enzymatic process to form polymers, which can be removed by precipitation with salts or condensation. The hybrid peroxidase catalysts exhibit three times higher activity than free HRP and are able to remove three times more phenol from water compared to free HRP under similar conditions. In addition, the hybrid catalysts reduce substrate inhibition and limit inactivation from reaction products, which are common problems with free or conventionally immobilized enzymes. Reusability is improved when the HRP–magnetic nanoparticle hybrids are supported on micron‐scale magnetic particles, and can be retained with a specially designed magnetically driven reactor. The performance of the hybrid catalysts makes them attractive for several industrial and environmental applications and their development might pave the way for practical applications by eliminating most of the limitations that have prevented the use of free or conventionally immobilized enzymes. 相似文献
127.
Phosphate Monoester Hydrolysis by Trinuclear Alkaline Phosphatase; DFT Study of Transition States and Reaction Mechanism 下载免费PDF全文
Alkaline phosphatase (AP) is a trinuclear metalloenzyme that catalyzes the hydrolysis of a broad range of phosphate monoesters to form inorganic phosphate and alcohol (or phenol). In this paper, by using density functional theory with a model based on a crystal structure, the AP‐catalyzed hydrolysis of phosphate monoesters is investigated by calculating two substrates, that is, methyl and p‐nitrophenyl phosphates, which represent alkyl and aryl phosphates, respectively. The calculations confirm that the AP reaction employs a “ping‐pong” mechanism involving two chemical displacement steps, that is, the displacement of the substrate leaving group by a Ser102 alkoxide and the hydrolysis of the phosphoseryl intermediate by a Zn2‐bound hydroxide. Both displacement steps proceed via a concerted associative pathway no matter which substrate is used. Other mechanistic aspects are also studied. Comparison of our calculations with linear free energy relationships experiments shows good agreement. 相似文献
128.
Porous CuO micro‐/nanostructures with clean surface, prepared through Cu2(OH)2CO3 precursor followed by calcination in air, were proven to be an effective peroxidase mimic. They can quickly catalyze oxidation of the peroxidase substrate 3,3′,5,5′‐tetramethylbenzidine (TMB) in the presence of H2O2, producing a blue color. The obtained porous CuO micro‐/nanostructure have potential application in wastewater treatment. The apparent steady‐state kinetic parameter was studied with TMB as the substrate. In addition, the potential application of the porous CuO in wastewater treatment was demonstrated with phenol‐containing water as an example. Such investigation not only confirms the intrinsic peroxidase‐like activity of micro‐/nanostructured CuO, but also suggests its potential application in wastewater treatment. 相似文献
129.
采用简便的水热法,获得了具有氧化酶催化特性的二氧化锰纳米管,研究了其对氧气(O2)氧化3,3',5,5'-四甲基联苯二胺(TMB)发生显色反应的催化性能,重点考察了常见金属离子对其活性的抑制作用。结果表明,能与MnO2表面发生特异性吸附络合作用的Pb2+的抑制作用最为显著。基于该抑制作用,建立了针对铅离子的高灵敏、快速检测新方法。结果显示,铅的线性范围为1.0×10-7~1.0×10-3 mol/L,检出限为3.0×10-8 mol/L。 相似文献
130.
Qiangzhe Zhang Dr. Ronnie H. Fang Dr. Weiwei Gao Dr. Liangfang Zhang 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(26):10547-10551
Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K-NP”). The L&K-NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in-coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K-NP structure, which voids toxicity associated with free molecules. In the study, L&K-NPs effectively inhibit PLA2-induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K-NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K-NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti-PLA2 approach. 相似文献