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January 30, 2014
Very Important Papers:
Active Efflux Influences the Potency of Quorum-Sensing Inhibitors in Pseudomonas aeruginosa
Joseph D. Moore, Joseph P. Gerdt, Nora R. Eibergen, and Helen E. Blackwell*
Small molecules capable of inhibiting bacterial cell--cell signaling, or quorum sensing (QS), are of significant interest as new chemical tools and potential anti-infective agents. Gram-negative bacteria predominately use N-acyl L-homoserine lactone (AHL) signals for QS. Now, Helen E. Blackwell (University of Wisconsin) and co-workers have shown that a variety of AHL-derived QS inhibitors in the pathogen Pseudomonas aeruginosa are substrates of its MexAB-OprM drug-efflux pump. In contrast, an aminobenzimidazole-type QS inhibitor does not display this efflux-induced reduction in potency. These results suggest that active efflux will need to be considered in the design of new QS modulators in P. aeruginosa and other bacteria.
Catalytic Scope of the Thiamine-Dependent Multifunctional Enzyme Cyclohexane-1,2-dione Hydrolase
Sabrina Loschonsky, Simon Waltzer, Sonja Fraas, Tobias Wacker, Susana L. A. Andrade, Peter M. H. Kroneck, and Michael Müller*
Cyclohexane-1,2-dione hydrolase (CDH) is a thiamine diphosphate-dependent enzyme that can accept a number of aromatic aldehydes that were previously hard to convert. Now, Michael Müller (Universität Freiburg) and co-workers have expressed CDH in E. coli and the recombinant CDH showed the same C–C bond-cleavage and C–C bond-formation activities as the wild-type enzyme. Furthermore, CDH catalyzes the asymmetric cross-benzoin reaction of aromatic aldehydes and pyruvate, up to quantitative conversion and 92–99% ee. On a semipreparative scale, the sterically demanding substrates 4-(tert-butyl)benzaldehyde and 2-naphthaldehyde, respectively, were transformed into the corresponding 2-hydroxyketone products in high yields. Additionally, certain benzaldehydes with electron-withdrawing substituents were identified as potential inhibitors of the C–C bond-formation activity of CDH. In a related paper, published simultaneously in ChemCatChem, M. Müller and co-workers also characterized the ability of CDH to catalyze the enantio-selective formation of (S)-acetoin by homocoupling of pyruvate, homocoupling of acetaldehyde, and cross-coupling of pyruvate and acetaldehyde.
Recently Published Articles
- Functional Investigations of Thromboxane Synthase (CYP5A1) in Lipid Bilayers of Nanodiscs
Prof. Aditi Das, Snehita Sri Varma, Christopher Mularczyk and Daryl D. Meling
Article first published online: 12 MAR 2014 | DOI: 10.1002/cbic.201300646
Changing lipid composition: CYP5A1 was incorporated into nanodiscs for functional studies. The redox potential and egress of small molecules from the active site were measured. Further, it was shown that CYP5A1 activity, and correspondingly, thromboxane synthase activity and conformation, changed dramatically depending on the lipid composition of the membrane bilayer.
- Repurposing the Chemical Scaffold of the Anti-Arthritic Drug Lobenzarit to Target Tryptophan Biosynthesis in Mycobacterium tuberculosis
Dr. Genevieve L. Evans, Dr. Swarna A. Gamage, Dr. Esther M. M. Bulloch, Prof. Edward N. Baker, Prof. William A. Denny and Assoc. Prof. J. Shaun Lott
Article first published online: 12 MAR 2014 | DOI: 10.1002/cbic.201300628
Restraint pays dividends: Lobenzarit (LBZ) features a bifurcated hydrogen bond that restrains its anionic groups to one side of the molecule. This intramolecular H bond is critical for the inhibitory potency of LBZ-like compounds against anthranilate phosphoribosyltransferase, a potential target for new antituberculosis agents. Small modifications to the scaffold resulted in complete rather than partial enzyme inhibition.
- Arginine Arrangement of Bacteriophage λ N-Peptide Plays a Role as a Core Motif in GNRA Tetraloop RNA Binding
Prof. Dr. Hiroyuki Furusawa, Dr. Shinobu Fukusho and Prof. Dr. Yoshio Okahata
Article first published online: 12 MAR 2014 | DOI: 10.1002/cbic.201300809
In vitro selection on QCM: To investigate the role of arginine arrangement in the arginine-rich motif (RNA binding domain) of bacteriophage λ N-peptide, in vitro selection of RNAs was carried out on N-model-peptide immobilized on a 27 MHz quartz-crystal microbalance (QCM) with monitoring of the selection processes.
- Rapid Flow-Based Peptide Synthesis
Mark D. Simon, Dr. Patrick L. Heider, Dr. Andrea Adamo, Alexander A. Vinogradov, Surin K. Mong, Xiyuan Li, Tatiana Berger, Rocco L. Policarpo, Chi Zhang, Dr. Yekui Zou, Dr. Xiaoli Liao, Dr. Alexander M. Spokoyny, Prof. Klavs F. Jensen and Prof. Bradley L. Pentelute
Article first published online: 11 MAR 2014 | DOI: 10.1002/cbic.201300796
Supercharged synthesis: Here we demonstrate a flow-based technology that uses low-cost components yet accelerates traditional Fmoc chemistry by an order of magnitude. Only 1.8 min per residue is required for chain assembly.
- A Dual Small-Molecule Rheostat for Precise Control of Protein Concentration in Mammalian Cells
Yu Hsuan Lin and Prof. Dr. Matthew R. Pratt
Article first published online: 11 MAR 2014 | DOI: 10.1002/cbic.201400006
Two controls are better than one: Using our traceless shield strategy and exploiting small-molecule control at both the transcriptional and post-translational levels, we have demonstrated that protein concentration can be precisely controlled in living cells over a 130-fold range. This approach is attractive for elucidation of the consequences of protein concentration in cell biology.