排序方式: 共有76条查询结果,搜索用时 798 毫秒
51.
Sabrina Castellano Dr. Ciro Milite Dr. Rino Ragno Dr. Silvia Simeoni Dr. Antonello Mai Prof. Vittorio Limongelli Dr. Ettore Novellino Prof. Ingo Bauer Dr. Gerald Brosch Prof. Astrid Spannhoff Dr. Donghang Cheng Dr. Mark T. Bedford Prof. Gianluca Sbardella Prof. 《ChemMedChem》2010,5(3):398-414
Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI‐1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis‐amidic moiety; 3) the introduction of a N‐containing basic moiety; and 4) the positional isomerization of the aminohydroxynaphthoic moiety. We have assessed the biological activity of these compounds against a panel of arginine methyltransferases (fungal RmtA, hPRMT1, hCARM1, hPRMT3, hPRMT6) and a lysine methyltransferase (SET7/9) using histone and nonhistone proteins as substrates. Molecular modeling studies for a deep binding‐mode analysis of test compounds were also performed. The bis‐carboxylic acid derivatives 1 b and 7 b emerged as the most effective PRMT inhibitors, both in vitro and in vivo, being comparable or even better than the reference compound (AMI‐1) and practically inactive against the lysine methyltransferase SET7/9. 相似文献
52.
Dr. Tea Pavkov-Keller Dr. Nina G. Schmidt Dr. Anna Żądło-Dobrowolska Prof. Dr. Wolfgang Kroutil Prof. Dr. Karl Gruber 《Chembiochem : a European journal of chemical biology》2019,20(1):88-95
C−C bond-forming reactions are key transformations for setting up the carbon frameworks of organic compounds. In this context, Friedel–Crafts acylation is commonly used for the synthesis of aryl ketones, which are common motifs in many fine chemicals and natural products. A bacterial multicomponent acyltransferase from Pseudomonas protegens (PpATase) catalyzes such Friedel–Crafts C-acylation of phenolic substrates in aqueous solution, reaching up to >99 % conversion without the need for CoA-activated reagents. We determined X-ray crystal structures of the native and ligand-bound complexes. This multimeric enzyme consists of three subunits: PhlA, PhlB, and PhlC, arranged in a Phl(A2C2)2B4 composition. The structure of a reaction intermediate obtained from crystals soaked with the natural substrate 1-(2,4,6-trihydroxyphenyl)ethanone together with site-directed mutagenesis studies revealed that only residues from the PhlC subunits are involved in the acyl transfer reaction, with Cys88 very likely playing a significant role during catalysis. These structural and mechanistic insights form the basis of further enzyme engineering efforts directed towards enhancing the substrate scope of this enzyme. 相似文献
53.
Synthesis of 3′‐Fluoro‐tRNA Analogues for Exploring Non‐ribosomal Peptide Synthesis in Bacteria
下载免费PDF全文
![点击此处可从《Chembiochem : a European journal of chemical biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Laura Iannazzo Guillaume Laisné Dr. Matthieu Fonvielle Dr. Emmanuelle Braud Dr. Jean‐Philippe Herbeuval Dr. Michel Arthur Dr. Mélanie Etheve‐Quelquejeu 《Chembiochem : a European journal of chemical biology》2015,16(3):477-486
Aminoacyl‐tRNAs (aa‐tRNAs) participate in a vast repertoire of metabolic pathways, including the synthesis of the peptidoglycan network in the cell walls of bacterial pathogens. Synthesis of aminoacyl‐tRNA analogues is critical for further understanding the mechanisms of these reactions. Here we report the semi‐synthesis of 3′‐fluoro analogues of Ala‐tRNAAla. The presence of fluorine in the 3′‐position blocks Ala at the 2′‐position by preventing spontaneous migration of the residue between positions 2′ and 3′. NMR analyses showed that substitution of the 3′‐hydroxy group by fluorine in the ribo configuration favours the S‐type conformation of the furanose ring of terminal adenosine A76. In contrast, the N‐type conformation is favoured by the presence of fluorine in the xylo configuration. Thus, introduction of fluorine in the ribo and xylo configurations affects the conformation of the furanose ring in reciprocal ways. These compounds should provide insight into substrate recognition by Fem transferases and the Ala‐tRNA synthetases. 相似文献
54.
Functional Characterization of MpaG′, the O‐Methyltransferase Involved in the Biosynthesis of Mycophenolic Acid
下载免费PDF全文
![点击此处可从《Chembiochem : a European journal of chemical biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dr. Wei Zhang Shaona Cao Dr. Li Qiu Dr. Fengxia Qi Zhong Li Ying Yang Dr. Shaohua Huang Fali Bai Prof. Dr. Changning Liu Prof. Dr. Xiaobo Wan Prof. Dr. Shengying Li 《Chembiochem : a European journal of chemical biology》2015,16(4):565-569
Mycophenolic acid (MPA, 1 ) is a clinically important immunosuppressant. In this report, a gene cluster mpa′ responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S‐adenosyl‐L ‐methionine‐dependent (SAM‐dependent) O‐methyltransferase encoded by the mpaG′ gene was functionally and kinetically characterized in vitro. MpaG′ catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6 ) to form 1 . It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis. 相似文献
55.
Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V,a Gilvocarcin‐Type Antitumor Agent
下载免费PDF全文
![点击此处可从《Chembiochem : a European journal of chemical biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jhong‐Min Chen Micah D. Shepherd Jamie Horn Markos Leggas Jürgen Rohr 《Chembiochem : a European journal of chemical biology》2014,15(18):2729-2735
Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure–activity relationships of the gilvocarcin group of antitumor antibiotics due to a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O‐methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2′‐OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important hydrogen bond donor for the interaction with histone H3, and converting 3′‐OH into an OCH3 group improved the bioactivity. Bis‐methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two hydrogen bond donors in the sugar are necessary for optimal binding. 相似文献
56.
57.
Jiang Y Morley KL Schrag JD Kazlauskas RJ 《Chembiochem : a European journal of chemical biology》2011,12(5):768-776
Acyl transfer is a key reaction in biosynthesis, including synthesis of antibiotics and polyesters. Although researchers have long recognized the similar protein fold and catalytic machinery in acyltransferases and hydrolases, the molecular basis for the different reactivity has been a long-standing mystery. By comparison of X-ray structures, we identified a different oxyanion-loop orientation in the active site. In esterases/lipases a carbonyl oxygen points toward the active site, whereas in acyltransferases a NH of the main-chain amide points toward the active site. Amino acid sequence comparisons alone cannot identify such a difference in the main-chain orientation. To identify how this difference might change the reaction mechanism, we solved the X-ray crystal structure of Pseudomonas fluorescens esterase containing a sulfonate transition-state analogue bound to the active-site serine. This structure mimics the transition state for the attack of water on the acyl-enzyme and shows a bridging water molecule between the carbonyl oxygen mentioned above and the sulfonyl oxygen that mimics the attacking water. A possible mechanistic role for this bridging water molecule is to position and activate the attacking water molecule in hydrolases, but to deactivate the attacking water molecule in acyl transferases. 相似文献
58.
Bräuer L Brandt W Schulze D Zakharova S Wessjohann L 《Chembiochem : a European journal of chemical biology》2008,9(6):982-992
The membrane-bound enzyme 4-hydroxybenzoic acid oligoprenyltransferase (ubiA) from E. coli is crucial for the production of ubiquinone, the essential electron carrier in prokaryotic and eukaryotic organisms. On the basis of previous modeling analyses, amino acids identified as important in two putative active sites (1 and 2) were selectively mutated. All mutants but one lost their ability to form geranylated hydroxybenzoate, irrespective of their being from active site 1 or 2. This suggests either that the two active sites are interrelated or that they are in fact only one site. With the aid of the experimental results and a new structure-based classification of prenylating enzymes, a relevant 3D model could be developed by threading. The new model explains the substrate specificities and is in complete agreement with the results of site-directed mutagenesis. The high similarity of the active fold of UbiA-transferase to that of 5-epi-aristolochene synthase (Nicotiana tabacum), despite a low homology, allows a hypothesis on a convergent evolution of these enzymes to be formed. 相似文献
59.
Dr. Philipp Ochtrop Stefan Ernst Prof. Dr. Aymelt Itzen Prof. Dr. Christian Hedberg 《Chembiochem : a European journal of chemical biology》2019,20(18):2336-2340
Site-specific protein functionalization has become an indispensable tool in modern life sciences. Here, tag-based enzymatic protein functionalization techniques are among the most versatilely applicable approaches. However, many chemo-enzymatic functionalization strategies suffer from low substrate scopes of the enzymes utilized for functional labeling probes. We report on the wide substrate scope of the bacterial enzyme AnkX towards derivatized CDP-choline analogues and demonstrate that AnkX-catalyzed phosphocholination can be used for site-specific one- and two-step protein labeling with a broad array of different functionalities, displaying fast second-order transfer rates of 5×102 to 1.8×104 m −1 s−1. Furthermore, we also present a strategy for the site-specific dual labeling of proteins of interest, based on the exploitation of AnkX and the delabeling function of the enzyme Lem3. Our results contribute to the wide field of protein functionalization, offering an attractive chemo-enzymatic tag-based modification strategy for in vitro labeling. 相似文献
60.
Dr. Mathew Sutherland Alice Li Anissa Kaghad Dimitrios Panagopoulos Dr. Fengling Li Dr. Magdalena Szewczyk Dr. David Smil Dr. Cora Scholten Dr. Léa Bouché Dr. Timo Stellfeld Dr. Cheryl H. Arrowsmith Dr. Dalia Barsyte Dr. Masoud Vedadi Dr. Ingo V. Hartung Dr. Holger Steuber Dr. Robert Britton Dr. Vijayaratnam Santhakumar 《ChemMedChem》2021,16(7):1116-1125
Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure-based design of a new class of alanine-containing 3-arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds. 相似文献