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931.
Well-resolved and unambiguous through-bond correlations and NOE data are crucial for high-quality protein structure determination by NMR. In this context, we present here (4, 3)D reduced dimensionality (RD) experiments: H(CC)CONH TOCSY and NOESY HNCO--which instead of (15)N shifts exploit the linear combination of (15)N(i) and (13)C'(i-1) shifts (where i is a residue number) to resolve the through-bond (1)H-(1)H correlations and through-space (1)H-(1)H NOEs. The strategy makes use of the fact that (15)N and (13)C' chemical shifts when combined linearly provide a dispersion which is better compared to those of the individual chemical shifts. The extended dispersion thus available in these experiments will help to obtain the unambiguous side chain and accurate NOE assignments especially for medium-sized alpha-helical or partially unstructured proteins [molecular weight (MW) between 12-15 kDa] as well as higher MW (between 15-25 kDa) folded proteins where spectral overlap renders inaccurate and ambiguous NOEs. Further, these reduced dimensionality experiments in combination with routinely used (15)N and (13)C' edited TOCSY and NOESY experiments will provide an alternative way for high-quality NMR structure determination of large unstable proteins (with very high shift degeneracy), which are not at all amenable to 4D NMR. The utility of these experiments has been demonstrated here using (13)C/(15)N labeled ubiquitin (76 aa) protein. 相似文献
932.
High‐temperature chlorination of C90‐containing fullerene fraction resulted in the isolation and X‐ray structural characterization of C90(1)Cl10/12, the first derivatives of a relatively unstable isomer D5h‐C90(1) with a nanotubular shape. In the crystal structure, three isomers of both C90(1)Cl10 and C90(1)Cl12 with similar chlorination patterns co‐crystallize in the same crystallographic site. Thus, in contrast to the previous reports, D5h‐C90(1) is present, though with a low abundance, in the fullerene soot produced by arc‐discharge method with undoped graphite rods. 相似文献
933.
Yi Yang Dr. Ji Liu Prof. Dr. Zhi Li 《Angewandte Chemie (International ed. in English)》2014,53(12):3120-3124
Terminal‐selective cytochrome P450pyr has been successfully engineered through directed evolution for the subterminal hydroxylation of alkanes with excellent regio‐ and enantioselectivity. A sensitive colorimetric high‐throughput screening (HTS) assay was developed for the measurement of both the regioselectivity and the enantioselectivity of a hydroxylation reaction. By using the HTS assay and iterative saturation mutagenesis, sextuple‐mutant P450pyrSM1 was created for the hydroxylation of n‐octane ( 1 ) to give (S)‐2‐octanol ( 2 ) with 98 % ee and >99 % subterminal selectivity. The engineered P450 is the first enzyme for this type of highly selective alkane hydroxylation, being useful for the C? H activation and functionalization of alkanes and the preparation of enantiopure alcohols. Molecular modeling provided structure‐based understanding of the fully altered regioselectivity and the excellent enantioselectivity. Another sextuple‐mutant P450pyrSM2 catalyzed the hydroxylation of propylbenzene ( 3 ) to afford (S)‐1‐phenyl‐2‐propanol ( 4 ) with 95 % ee and 98 % subterminal selectivity. 相似文献
934.
Dr. Ryan J. Rafferty Robert W. Hicklin Katherine A. Maloof Prof. Paul J. Hergenrother 《Angewandte Chemie (International ed. in English)》2014,53(1):220-224
Many compound screening collections are populated by members that possess a low degree of structural complexity. In an effort to generate compounds that are both complex and diverse, we have developed a strategy that uses natural products as a starting point for complex molecule synthesis. Herein we apply this complexity‐to‐diversity approach to abietic acid, an abundant natural product used commercially in paints, varnishes, and lacquers. From abietic acid we synthesize a collection of complex (as assessed by fraction of sp3‐hybridized carbons and number of stereogenic centers) and diverse (as assessed by Tanimoto analysis) small molecules. The 84 compounds constructed herein, and those created through similar efforts, should find utility in a variety of biological screens. 相似文献
935.
Golotvin SS Vodopianov E Pol R Lefebvre BA Williams AJ Rutkowske RD Spitzer TD 《Magnetic resonance in chemistry : MRC》2007,45(10):803-813
A method for structure validation based on the simultaneous analysis of a 1D (1)H NMR and 2D (1)H - (13)C single-bond correlation spectrum such as HSQC or HMQC is presented here. When compared with the validation of a structure by a 1D (1)H NMR spectrum alone, the advantage of including a 2D HSQC spectrum in structure validation is that it adds not only the information of (13)C shifts, but also which proton shifts they are directly coupled to, and an indication of which methylene protons are diastereotopic. The lack of corresponding peaks in the 2D spectrum that appear in the 1D (1)H spectrum, also gives a clear picture of which protons are attached to heteroatoms. For all these benefits, combined NMR verification was expected and found by all metrics to be superior to validation by 1D (1)H NMR alone. Using multiple real-life data sets of chemical structures and the corresponding 1D and 2D data, it was possible to unambiguously identify at least 90% of the correct structures. As part of this test, challenging incorrect structures, mostly regioisomers, were also matched with each spectrum set. For these incorrect structures, the false positive rate was observed as low as 6%. 相似文献
936.
合成低碳醇超细Mo-Co-K催化剂的TPD研究 总被引：1，自引：3，他引：1
近年来 ,Ｍｏ基催化剂由于其独特的耐硫性而在各种合成低碳醇催化剂体系中倍受青睐。许多研究表明 ,以Ｃｏ作为Ｍｏ基催化剂的第二组分可明显改善其催化合成低碳醇的反应性能[1～ 4] 。一般认为 ,Ｋ是这类催化剂通用的促进剂[1,3 ,5,6] 。我们曾经报道[7] ,还原态超细Ｍｏ Ｃｏ Ｋ催化剂具有优良的合成低碳醇性能。同时 ,催化剂的Ｃｏ Ｍｏ比对其合成低碳醇性能具有显著的影响。为了解这种影响的原因 ,本文运用ＴＰＤ技术对此类催化剂进行了研究。催化剂经还原后 ,在催化剂表面即形成了不同的吸附中心[8] 。了解这些不同的吸附中心 ,对于研… 相似文献
937.
The prominence of endogenous peptide ligands targeted to receptors makes peptides with the desired binding activity good molecular scaffolds for drug development. Minor modifications to a peptide's primary sequence can significantly alter its binding properties with a receptor, and screening collections of peptide mutants is a useful technique for probing the receptor–ligand binding domain. Unfortunately, the combinatorial growth of such collections can limit the number of mutations which can be explored using structure‐based molecular docking techniques. Genetic algorithm managed peptide mutant screening (GAMPMS) uses a genetic algorithm to conduct a heuristic search of the peptide's mutation space for peptides with optimal binding activity, significantly reducing the computational requirements of the virtual screening. The GAMPMS procedure was implemented and used to explore the binding domain of the nicotinic acetylcholine receptor (nAChR) ‐isoform with a library of 64,000 α‐conotoxin (α‐CTx) MII peptide mutants. To assess GAMPMS's performance, it was compared with a virtual screening procedure that used AutoDock to predict the binding affinity of each of the α‐CTx MII peptide mutants with the ‐nAChR. The GAMPMS implementation performed AutoDock simulations for as few as 1140 of the 64,000 α‐CTx MII peptide mutants and could consistently identify a set of 10 peptides with an aggregated binding energy that was at least 98% of the aggregated binding energy of the 10 top peptides from the exhaustive AutoDock screening. © 2015 Wiley Periodicals, Inc. 相似文献
938.
Dr. Gun‐Hee Kim Dr. Debasish Halder Jinhong Park Prof. Dr. Wan Namkung Prof. Dr. Injae Shin 《Angewandte Chemie (International ed. in English)》2014,53(35):9271-9274
Reported herein are two imidazole‐based small molecules, termed neurodazine (Nz) and neurodazole (Nzl), which induce neuronal differentiation of pluripotent P19 cells. Their ability to induce neurogenesis of P19 cells is comparable to that of retinoic acid. However, Nz and Nzl were found to be more selective neurogenesis inducers than retinoic acid owing to their unique ability to suppress astrocyte differentiation of P19 cells. Our results also show that Nz and Nzl promote production of physiologically active neurons because P19‐cell‐derived neurons induced by these substances have functional glutamate responsiveness. The present study suggests that Nz and Nzl could serve as important chemical tools to induce formation of specific populations of neuronal cell types from pluripotent cells. 相似文献
939.
Zhi‐Rong Tan Yao Chen Ji‐Ye Yin Jing Yu Jian Qu Hong‐Hao Zhou Zhao‐Qian Liu 《Biomedical chromatography : BMC》2014,28(2):197-203
A sensitive and high‐throughput inhibition screening liquid chromatography–mass spectrometry (LC‐MS/MS) method was developed and validated for the simultaneous quantification of five probe metabolites (7‐hydroxycoumarin, CYP2A6; 4‐hydroxytolbutamide, CYP2C9; 4′‐hydroxymephenytoin, CYP2C19; α‐hydroxymetoprolol, CYP2D6; and 1‐hydroxymidazolam, CYP3A4) for in vitro cytochrome P450 activity determination in human liver microsome and recombinant. All the metabolites and the internal standard, tramadol, were separated on a Waters 2695 series liquid chromatograph with a Phenomenex Luna C18 column (150 × 2.0 mm, 5 µm). Quality control samples and a positive control CYP inhibitor were included in the method. The IC50 values determined for typical CYP inhibitors were reproducible and in agreement with the literature. The method was selective and showed good accuracy (99.13–103.37%), and inter‐day (RSD < 6.20%) and intra‐day (RSD < 6.13%) precision. Also, the incubation extracts of the sample were stable at room temperature (20 °C) for 48 h and for 96 h in the autosampler (4 °C). The presented method is the first HPLC‐MS/MS method of this combination for simultaneous detection of the five metabolites 7‐hydroxycoumarin, 4‐hydroxytolbutamide, 4′‐hydroxymephenytoin, α‐hydroxymetoprolol and 1‐hydroxymidazolam in a single‐run process. It is possible that the high‐quality and ‐throughput cocktail provides suitable information in drug discovery and screening for new drug entities. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
940.
Dr. Guang‐Yu Yang Dr. Caishun Li Dr. Michael Fischer Prof. Christopher W. Cairo Prof. Yan Feng Prof. Stephen G. Withers 《Angewandte Chemie (International ed. in English)》2015,54(18):5389-5393
Gangliosides are important signaling molecules in the cell membrane and are processed by several enzymes. Deficiencies in these enzymes can cause human lysosomal storage diseases. Building an understanding of the pathways of glycosphingolipid catabolism requires methods for the analysis of these enzymatic activities A GM3‐derived FRET probe was synthesized chemoenzymatically for the detection and quantitation of a range of ganglioside‐degrading enzymes, both in cell lysates and in living cells. This is the first substrate that enables the ratiometric fluorogenic assay of sphingolipid ceramide N‐deacylase and endoglycoceramidase and can detect and localize neuraminidase activity in living cells. It is therefore a valuable tool for building a better understanding of membrane‐confined enzymology. It also enables the robust and reliable assay of ganglioside‐degrading enzymes in a microtiter plate, thus opening the door to screening for novel or engineered biocatalysts or for new inhibitors. 相似文献