Fr Francium

Small wonder:Atrop-abyssomicin C is a small, yet complex spirotetronate (see scheme) that is active against Gram-positive bacteria, such as MRSA. Feeding studies and genetic manipulation of its producer, Verrucosispora maris AB-18-032, for the first time give insight into its biosynthesis and demonstrate how closely related the members of this important class of molecules are.

The cover picture shows the effects of individual regions of IAPP-GI, a nonamyloidogenic mimic of the type 2 diabetes islet amyloid polypeptide (IAPP), on amyloid formation of the Alzheimer's disease amyloid β-peptide (Aβ). IAPP-GI has previously been found to bind Aβ with high affinity and to block its cytotoxic amyloidogenesis. Moreover, the Aβ-IAPP cross-amyloid interaction suppresses cytotoxic self-association by both polypeptides and might be a molecular link between the two diseases. Here the 37-residue IAPP-GI was dissected into shorter segments including the two hot-spot regions of the Aβ-IAPP(IAPP-GI) interaction interface IAPP(8–18) (pink) and IAPP(22–28)-GI (green) and the N- or C-terminal regions IAPP(1–7) (light blue) and IAPP(30–37) (dark blue). Only IAPP-GI and IAPP(1–28)-GI inhibited Aβ cytotoxic self-assembly and amyloidogenesis whereas all other segments even the ones containing hot-spot regions, such as IAPP(8–28)-GI, were unable to inhibit uncovering thus important molecular determinants of the IAPP-GI(IAPP) mediated inhibition of Aβ self-assembly. For more details, see the paper by A. Kapurniotu et al. on p. 1313 ff.

DNA methylation is involved in the regulation of gene expression and plays an important role in normal developmental processes and diseases, such as cancer. DNA methyltransferases are the enzymes responsible for DNA methylation on the position 5 of cytidine in a CpG context. In order to identify and characterize novel inhibitors of these enzymes, we developed a fluorescence-based throughput screening by using a short DNA duplex immobilized on 96-well plates. We have screened 114 flavones and flavanones for the inhibition of the murine catalytic Dnmt3a/3L complex and found 36 hits with IC₅₀ values in the lower micromolar and high nanomolar ranges. The assay, together with inhibition tests on two other methyltransferases, structure–activity relationships and docking studies, gave insights on the mechanism of inhibition. Finally, two derivatives effected zebrafish embryo development, and induced a global demethylation of the genome, at doses lower than the control drug, 5-azacytidine.

Screen shots: A set of flavones and flavanones is described as a new family of nanomolar DNA methyltransferase inhibitors. Structure–activity relationships, enzymatic competition and docking studies (see figure) have provided insights on their mode of action. Two inhibitors effected zebrafish development in a similar fashion to the reference drug, 5-azacytidine.

Fluorogenic protein-labeling techniques have been successfully used in live-cell imaging. Fluorescence derived from specific labeling can monitor the localization of proteins. Newly developed chemical techniques have addressed such specific incorporation of probes in the physiological environment. We conclude that some recent promising switching techniques should provide further molecular functional exploitation in vivo.