Structural Insights into the Neuroprotective acting Carbonyl Reductase Sniffer of Drosophila melanogaster

In vivo studies with the fruit fly Drosophila melanogaster have shown that the Sniffer protein prevents age dependent and oxidative stress induced neurodegenerative processes. Sniffer is a NADPH dependent carbonyl reductase belonging to the enzyme family of short chain dehydrogenases reductases SDRs . The crystal structure of the homodimeric Sniffer protein from Drosophila melanogaster in complex with NADP has been determined by multiple wavelength anomalous dispersion and refined to a resolution of 1.75 . The observed fold represents a typical dinucleotide binding domain as detected for other SDRs. With respect to the cofactor binding site and the region referred to as substrate binding loop, the Sniffer protein shows a striking similarity to the porcine carbonyl reductase PTCR . This loop, in both Sniffer and PTCR, is substantially shortened compared to other SDRs. In most enzymes of the SDR family this loop adopts a well defined conformation only after substrate binding and remains disordered in the absence of any bound ligands or even if only the dinucleotide cofactor is bound. In the structure of the Sniffer protein, however, the conformation of this loop is well defined, although no substrate is present. Molecular modeling studies provide an idea of how binding of substrate molecules to Sniffer could possibly occu

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Available from TIB Hannover: F03B128+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Bildung und Forschung, Berlin (Germany)DEGerman

Hollow SiO2 Microspheres Produced by Coating Yeast Cells

Hollow silica microspheres were produced by coating yeast cells with amorphous SiO2. In the pptn. reaction, yeast cells of Saccharomyces cerevisiae were used as a biol. template. The silica shell was synthesized by the hydrolysis of tetraethylorthosilicate (TEOS) in water-alc. mixts. as solvent using ammonia as a catalyst according to the Stoeber process. The hollow microspheres were characterized by means of SEM and TGA. Both smooth and textured coatings were prepd. The biol. template can be removed by calcining, after which the particle morphol. persists. Addnl., d. and light scattering coeffs. of the pigment were measured

IspE inhibitors identified by a combination of in silico and in vitro high-throughput screening

CDP-ME kinase (IspE) contributes to the non-mevalonate or deoxy-xylulose phosphate (DOXP) pathway for isoprenoid precursor biosynthesis found in many species of bacteria and apicomplexan parasites. IspE has been shown to be essential by genetic methods and since it is absent from humans it constitutes a promising target for antimicrobial drug development. Using in silico screening directed against the substrate binding site and in vitro high-throughput screening directed against both, the substrate and co-factor binding sites, non-substrate-like IspE inhibitors have been discovered and structure-activity relationships were derived. The best inhibitors in each series have high ligand efficiencies and favourable physico-chemical properties rendering them promising starting points for drug discovery. Putative binding modes of the ligands were suggested which are consistent with established structure-activity relationships. The applied screening methods were complementary in discovering hit compounds, and a comparison of both approaches highlights their strengths and weaknesses. It is noteworthy that compounds identified by virtual screening methods provided the controls for the biochemical screens