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941.
Jos H.M. Lange Martina A.W. van der Neut Henri C. Wals Gijs D. Kuil Alice J.M. Borst Arie Mulder Arnold P. den Hartog Hicham Zilaout Wouter Goutier Herman H. van Stuivenberg Bernard J. van Vliet 《Bioorganic & medicinal chemistry letters》2010,20(3):1084-1089
The synthesis and structure–activity relationship studies of imidazoles are described. The target compounds 6–20 represent a novel chemotype of potent and CB2/CB1 selective cannabinoid CB2 receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable log P and calculated polar surface area values. Compound 12 exhibited the highest CB2 receptor affinity (Ki = 1.03 nM) in this series, as well as the highest CB2/CB1 subtype selectivity (>9708-fold). 相似文献
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Michailidis Michail Karagiannis Evangelos Tanou Georgia Samiotaki Martina Tsiolas George Sarrou Eirini Stamatakis George Ganopoulos Ioannis Martens Stefans Argiriou Anagnostis Molassiotis Athanassios 《Plant molecular biology》2020,104(6):597-614
Plant Molecular Biology - This work provides the first system-wide datasets concerning metabolic changes in calcium-treated fruits, which reveal that exogenously applied calcium may specifically... 相似文献
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Rothmeier Louisa Marie Sahm René Watermann Burkard Grabow Karsten Koester Meike Cichy Anna Martens Andreas 《Hydrobiologia》2021,848(10):2569-2578
Hydrobiologia - The introduction of non-indigenous organisms in new areas in the context of host-parasite interactions is still poorly understood. This study aimed at a parasitological and... 相似文献
949.
Hanne K. J. Gonnissen Claire Mazuy Femke Rutters Eveline A. P. Martens Tanja C. Adam Margriet S. Westerterp-Plantenga 《PloS one》2013,8(8)
Circadian misalignment affects total sleep time, but it may also affect sleep architecture. The objectives of this study were to examine intra-individual effects of circadian misalignment on sleep architecture and inter-individual relationships between sleep stages, cortisol levels and insulin sensitivity. Thirteen subjects (7 men, 6 women, age: 24.3±2.5 y; BMI: 23.6±1.7 kg/m2) stayed in a time blinded respiration chamber during three light-entrained circadian cycles (3x21h and 3x27h) resulting in a phase advance and a phase delay. Sleep was polysomnographically recorded. Blood and salivary samples were collected to determine glucose, insulin and cortisol concentrations. Intra-individually, a phase advance decreased rapid eye movement (REM) sleep and slow-wave sleep (SWS), increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. A phase delay increased REM sleep, decreased stage 2 sleep, increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. Moreover, circadian misalignment changed REM sleep distribution with a relatively shorter REM sleep during the second part of the night. Inter-individually, REM sleep was inversely associated with cortisol levels and HOMA-IR index. Circadian misalignment, both a phase advance and a phase delay, significantly changed sleep architecture and resulted in a shift in rem sleep. Inter-individually, shorter REM sleep during the second part of the night was associated with dysregulation of the HPA-axis and reduced insulin sensitivity.
Trial Registration: International Clinical Trials Registry Platform NTR2926 http://apps.who.int/trialsearch/ 相似文献
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Sebastian Tanco Julia Lorenzo Javier Garcia-Pardo Sven Degroeve Lennart Martens Francesc Xavier Aviles Kris Gevaert Petra Van Damme 《Molecular & cellular proteomics : MCP》2013,12(8):2096-2110
Through processing peptide and protein C termini, carboxypeptidases participate in the regulation of various biological processes. Few tools are however available to study the substrate specificity profiles of these enzymes. We developed a proteome-derived peptide library approach to study the substrate preferences of carboxypeptidases. Our COFRADIC-based approach takes advantage of the distinct chromatographic behavior of intact peptides and the proteolytic products generated by the action of carboxypeptidases, to enrich the latter and facilitate its MS-based identification. Two different peptide libraries, generated either by chymotrypsin or by metalloendopeptidase Lys-N, were used to determine the substrate preferences of human metallocarboxypeptidases A1 (hCPA1), A2 (hCPA2), and A4 (hCPA4). In addition, our approach allowed us to delineate the substrate specificity profile of mouse mast cell carboxypeptidase (MC-CPA or mCPA3), a carboxypeptidase suggested to function in innate immune responses regulation and mast cell granule homeostasis, but which thus far lacked a detailed analysis of its substrate preferences. mCPA3 was here shown to preferentially remove bulky aromatic amino acids, similar to hCPA2. This was also shown by a hierarchical cluster analysis, grouping hCPA1 close to hCPA4 in terms of its P1 primed substrate specificity, whereas hCPA2 and mCPA3 cluster separately. The specificity profile of mCPA3 may further aid to elucidate the function of this mast cell carboxypeptidase and its biological substrate repertoire. Finally, we used this approach to evaluate the substrate preferences of prolylcarboxypeptidase, a serine carboxypeptidase shown to cleave C-terminal amino acids linked to proline and alanine.Carboxypeptidases (CPs)1 catalyze the release of C-terminal amino acids from proteins and peptides (1, 2), and are grouped according to the chemical nature of their catalytic site. Accordingly, there are three types of carboxypeptidases: metallocarboxypeptidases (MCPs), serine carboxypeptidases (SCPs), and cysteine carboxypeptidases. CPs can also be classified based on their substrate specificity; CPs that prefer hydrophobic C-terminal amino acids (A-like MCPs or C-type SCPs), those that cleave C-terminal basic residues (B-like MCPs or D-type SCPs), those that recognize substrates with C-terminal aspartate or glutamate residues, and other CPs that display a broad substrate specificity (3, 4).CPs were initially considered as degrading enzymes associated with protein catabolism. However, accumulating evidence demonstrates that some CPs are (more) selective and play key roles in controlling various biological processes (2, 5). Angiotensin-converting enzyme 2 (ACE2), a MCP homolog of angiotensin-converting enzyme (ACE) that belongs to the M2 family of proteolytic enzymes according to the MEROPS classification, is a potent negative regulator of the renin-angiotensin system and plays a key role in maintaining blood pressure homeostasis. ACE2 cleaves off a C-terminal phenylalanine thereby converting angiotensin II to the heptapeptide angiotensin-(1–7), a peptide hormone that opposes the vasoconstrictor and proliferative actions of angiotensin II (6). Cathepsin A, a lysosomal SCP, is also believed to function in blood pressure regulation, in this case through its action against vasoactive peptides like endothelin-1 or angiotensin I (7). Human carboxypeptidase A4 (hCPA4), a MCP from the M14 family, presumably functions in neuropeptide processing and was linked to prostate cancer aggressiveness (8).Besides their biological importance, CPs are also exploited in biotechnological and biomedical applications. Carboxypeptidase B (CPB) for instance, is a M14 MCP used for manufacturing recombinant human insulin. Recombinant preproinsulin is enzymatically processed in vitro by pancreatic trypsin and carboxypeptidase B to generate the active insulin form (9). Further, carboxypeptidase digestion has been used for determining the C-terminal sequence of purified proteins or peptides. The most popular CPs being the SCPs C, P and Y (10). In addition, the food industry uses different SCPs to process protein products to reduce their bitter taste (11–13).Identifying a protease''s specificity and its natural substrates provides key information to understanding the molecular role of proteases (14, 15). Moreover, determination of a protease''s specificity also provides a framework for the design of selective probes and potent and selective inhibitors (16). Although several factors impact on substrate selection, a key factor is the complementarity of a protease binding site with specific substrate side-chains.Several approaches for determining protease substrate specificity based on peptide libraries have been developed, including substrate phage/bacterial display libraries, peptide microarrays, positional-scanning peptide libraries, mixture-based peptide libraries, and proteome-derived peptide libraries (17). The latter were more recently introduced by Schilling et al. (18) and make use of natural peptide libraries generated by proteolysis of a model proteome using a specific protease (e.g. trypsin, chymotrypsin). Such peptide libraries are subsequently digested by a protease of interest and the resulting neo-N-terminal products are enriched and identified following LC-MS/MS analyses. This technology allows profiling of the substrate specificity of endoproteases and aminopeptidases. However, viewing the fact that only C-terminal cleavage products are isolated by this method, it cannot be used to study CPs because their resulting primed site cleavage products are typically only a single amino acid and thus are not compatible for subsequent LC-MS/MS based identification.Currently, two different peptide-centric degradomic approaches (19) are available for CP substrate profiling. Recently, a multiplex substrate profiling by mass spectrometry (MSP-MS) method, which applies mass spectrometry-based peptide sequencing to detect cleavage products in a mixture of synthetic peptides, was used to determine the substrate preferences of prolylcarboxypeptidase (PRCP) (20). Further, peptidomic studies have made use of natural peptides isolates from cells and tissues as natural substrate pools to test cleavages by CPs (8, 21, 22). In this list of degradomic approaches, we can additionally consider the protein-centric positional proteomics approaches; C-terminal COFRADIC (23) and C-TAILS (24), capable of identifying in vivo CP proteolytic events, based on the identification of protein neo-C termini.We here exploited the COFRADIC technology (25) and developed a proteome-derived carboxypeptidase peptide library assay that was used to determine the substrate specificity profile of 5 selected human carboxypeptidases: 4 enzymes belonging to the MCP family and PRCP, which is a SCP. Given that MCPs are the most studied and thus a highly relevant group of CPs, the human metallocarboxypeptidases A4 (hCPA4), A2 (hCPA2), and A1 (hCPA1) were used as model CPs. Two different peptide libraries, created using chymotrypsin or metalloendopeptidase Lys-N as peptide library generating proteases, were used to extensively profile the proteolytic substrate specificities of these MCPs. In addition, we profiled the substrate preferences for the yet uncharacterized mast cell carboxypeptidase (MC-CPA or mCPA3). Besides, using Lys-N proteome-derived peptide libraries and making use of shorter protease incubation times, information on sequential cleavages of these enzymes could be obtained. Finally, this assay was additionally applied to PRCP, a pharmaceutically relevant SCP that differs from MCPs in its enzymatic characteristics, further demonstrating the more universal applicability of our method. 相似文献