A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of beta-N-acetylglucosaminidases

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of beta-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human beta-hexosaminidase, as well as two bacterial beta-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency.     

Flexing and stretching in nonribosomal Peptide synthetases

Re-engineering of nonribosomal peptide synthetase molecular assembly lines has been hampered by a lack of detailed knowledge concerning inter-domain substrate transfer. Recent structural studies of catalytically relevant domain-domain interactions provide valuable insights into this problem (Liu et?al., 2011; Sundlov et?al., 2012 [in this issue of Chemistry & Biology]).     

Gaining insight into the inhibition of glycoside hydrolase family 20 exo-β-N-acetylhexosaminidases using a structural approach

One useful methodology that has been used to give insight into how chemically synthesized inhibitors bind to enzymes and the reasons underlying their potency is crystallographic studies of inhibitor-enzyme complexes. Presented here is the X-ray structural analysis of a representative family 20 exo-β-N-acetylhexosaminidase in complex with various known classes of inhibitor of these types of enzymes, which highlights how different inhibitor classes can inhibit the same enzyme. This study will aid in the future development of inhibitors of not only exo-β-N-acetylhexosaminidases but also other types of glycoside hydrolases.     

Measurements of the acoustic target strengths of fish in dorsal aspect,including swimbladder resonance

The need for measurements of the acoustic target strength of fish is discussed. The phenomenon of swimbladder resonance of small deep ocean fish is well known and is a useful means of estimating their sizes. For larger commercial fish in shallower seas the resonant frequency is much lower and resonance is very difficult to observe in the field. A method of observing and measuring the swimbladder resonance of a captive live fish in controlled conditions is described, and results on several gadoids are given. Reasons for the observed resonant frequencies being higher than predicted are given; the damping of resonance is high, which is expected. Application of these results to acoustic sizing at sea appears remote. They are relevant, however, to studies of low-frequency sound propagation, and the experimental technique is offered as a useful tool in physiological studies involving swim-bladder function.     

Milch und Milchprodukte

Ohne Zusammenfassung     

Rules of Macrocycle Topology: A [13]‐Macrodilactone Case Study

Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large‐ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]‐macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic “ribbon” shape is adopted by the [13]‐macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle‐biomolecule interactions and for the preparation of macrocycles with designed properties and activities.     

Structural comparisons of the aggregates of tobacco mosaic virus protein

The coat protein of tobacco mosaic virus forms numerous aggregates, including the small A-protein, the disk, and two helical forms. The structures of the disk, the helical protein forms, and the virus are compared. Most of the differences are in the conformation of the chain between residues 89 and 113, which lies in the region of protein at the center of the virus, inside the RNA. It is disordered in the disk, but has a fixed conformation in the virus and the protein helices. The differences between the virus and the two helical protein forms are largely in the conformations of arginines and carboxylic acids in this region.