ChemBioChem

The cover picture shows the effects of the polyketide kendomycin on the model mammalian cell lines U-937 and PtK₂. Kendomycin induces a multiplicity of cellular responses, including up-regulation of stress-response proteins, vacuolization of the endoplasmic reticulum, accumulation of ubiquitinylated proteins and apoptosis. These effects are consistent with inhibition of the proteasome, an activity that kendomycin also exhibits in vitro. Kendomycin thus represents a new structural type of proteasome inhibitor, with potential utility both in chemical genetics and therapy. Further details can be found in the article by R. Müller et al. on p. 1261 ff.

Cys no longer required. A recent report from the Muir group describes access to monoubiquitylated histone peptides by expressed protein ligation (EPL). This convenient strategy employs a photolabile thiol auxiliary that allows site-specific ubiquitylation of a Lys side chain and removes need for a Cys residue at the ligation site.

Through the wire. We have investigated the potential effects of silicon nanowires (SiNW-SiO₂) and SiNWs functionalized with carboxylic groups (SiNW-COOH) on restriction endonucleases and Taq DNA polymerase. The results show that these SiNWs can inhibit enzyme activity (lower band in gel). Our findings suggest that this could be due to chemical interactions between the functional groups on SiNWs and the enzymes.

Designer nanoparticle conjugates. Locked nucleic acid (LNA) oligonucleotides can be used to functionalize nanoparticles to yield a novel conjugate that is highly stable and has a remarkably high affinity for complementary nucleic acids. When tested in a cell line model, these conjugates were found to be effective at controlling survivin gene expression.

A short interruption. Although the importance of Mediator in transcriptional regulation is recognized, little is known about the protein–protein interactions in this complex. Here we report a peptide that disrupts the association of Mediator components Med14(Rgr1) and Med15(Gal11) and will be a valuable tool for elucidating the functional role of these interactions.

Mellow gold. Toxicogenomics of nanoparticles can expose subtle yet clinically relevant alterations in the intracellular environment that arise from downstream effects of nanoparticle accumulation inside cells. Genome-wide expression profiling by using DNA microarrays revealed that internalization of gold nanoparticles is not associated with gross changes in transcription in HeLa cells (see figure).

The terminators. A chain-termination approach was employed to rationally design monosaccharide derivatives as inhibitors of chitin biosynthesis by replacement of the 4-hydroxyl group of N-acetyl glucosamine monomers. Antifungal activity was observed for a variety of acylated monosaccharide and oxazoline derivatives by means of fungal-spore germination and adhesion assays.

The ties that bind. A biosensor based on modulation of single ion-channel activity, with the ability to detect analytes in the micromolar range was devised. Ion channels were interfaced to a gold surface and reconstituted into tethered bilayer lipid membranes (tBLMs; see scheme). Using this method we obtained single channel activities from the synthetic ion channel, M2δ, and the Ca²⁺-activated K⁺ ion channel.

Flexibility exercise. NMR studies of the Aβ(1–40) and -(1–42) peptides demonstrated that structural, dynamic properties of soluble monomeric Aβ peptides are highly correlated to the amyloid fibril structure. In particular, fast-timescale dynamics were found to be an additional critical parameter in identifying the more crucial aggregation-prone segments of Aβ peptides (see figure). This method can be applied to investigate amyloidogenic and nonamyloidogenic properties of disordered states of proteins.

A 2-symbol-2-state finite automaton that utilized linear double-stranded DNA input molecules generated a plasmid that upon transformation and expression in E. coli on X-gal medium produced either blue or white bacterial colonies, depending on the input.

The first macrocyclic polyketide proteasome inhibitor. Kendomycin is a macrocyclic polyketide recently discovered in several Streptomyces species. We provide evidence here that kendomycin's potent antiproliferative activity derives from inhibition of the proteasome. Kendomycin therefore represents the founding member of a new class of proteasome inhibitors with promise both in therapy and in chemical genetics.

Getting the bit on the side. Further insights into the myxovirescin megasynthetase have been revealed on systematic deletion of a series of discrete genes, whose products have been suggested to participate in the formation of the unusual methoxymethyl and ethyl side groups of this antibiotic.

Cleave and keep connected. Maps of cross-links between amino acid in close proximity can validate 3D models of protein structures. With a new amine-specific cross-linking agent, a particular set of two competing reactions of cross-linked peptides can be induced that forms the basis of an analytical strategy to facilitate the mapping of cross-links.

MAGL studies. Our highly purified human monoacylglycerol lipase (MAGL), a key enzyme of the endocannabinoid system, enables the precise evaluation of MAGL inhibitors—compounds with promising therapeutic potential—and should help in the future structural characterization of MAGL.

High efficiency. FgaPT2, a 4-dimethylallyltryptophan synthase from Aspergillus fumigatus, was used as a tool for chemoenzymatic synthesis. FgaPT2 accepted 17 of 37 indole derivatives as substrates, with conversion rates of up to 99.7 % being observed for eight selected indole derivatives. NMR and MS analyses proved that the prenylation was regiospecific at position 4 of the indole moiety. The kinetic parameters of nine indole derivatives were determined.

Remodeled. The crystal structure and functions of bromodomain of human BRG1 protein are reported. BRG1 is the central ATPase of the SWI/SNF chromatin-remodeling complex. In addition to the typical all-α-helical fold that is seen in bromodomains, we observed for the first time a small β-sheet in the ZA loop region of the BRG1 protein and differences in the acetyl-lysine binding site.

The HO^. generation of several biologically relevant copper–peptide complexes, including amyloid-β could be correlated to their redox potential and coordination chemistry. The copper complex of the highly toxic amyloid-β1–42 showed a HO^. production five times higher than that of the less toxic amyloid-β1–40; this could be associated with the presence of an oligomeric state of copper–amyloid-β1–42.