Volume 6 Issue 2, February 2010

Phosphoinositide 3-OH kinases (PI(3)Ks) are important lipid signaling enzymes and exciting drug targets for a number of human diseases. The first, much anticipated crystal structure of the delta isoform of PI(3)K provides surprising new insights into the selectivity of inhibitors for this versus other PI(3)K isoforms and facilitates the design of improved drugs.

Reprogramming cell fates might cure or ameliorate many diseases. New results show that chemical reprogramming can be used in living animals to restore missing cell types.

Antibiotics can break down through the action of enzymes or through non-enzymatic processes. In the case of tetracycline, this drug 'debris' can have unexpected biological activities, including selection against resistance.

A process in which peptide nucleic acids may be used for in vitro evolution has been developed. This method can offer enormous opportunities to evolve stable, non-natural molecules for therapeutic applications.

The tetronate ring appears in several natural products, but the biosynthetic path to this structure has proven elusive. Reconstitution of a polyketide assembly line and in vitro assays with a chemically synthesized intermediate now point to a single enzyme as catalyzing ring formation.

Compounds targeting the ERK/MAPK pathway in C. elegans could influence germ cell fate, inducing oocyte differentiation of stem cells in worms that only make sperm. The oocytes generated were functional, as they were able to generate embryos and produce viable offspring.

Although tetracycline selects for tetracycline-resistant bacterial strains, degradation products of tetracycline are now shown to select for tetracycline-sensitive strains, providing a potential mechanism for the observed coexistence of antibiotic-sensitive and antibiotic-resistant bacteria in the environment.

Na⁺and substrate symport through Tyt1, a prokaryotic neurotransmitter:sodium symporter, requires an inversely oriented H⁺ gradient, maintaining an ionic counterbalance during neurotransmitter translocation that is facilitated by negatively charged amino acid residues.

Upregulation of PI(3)K signaling pathways is implicated in many diseases, and a number of inhibitors are currently in clinical development. The structure of a PI(3)Kδ kinase domain, along with co-complexes with a diverse range of inhibitors, reveals new insights into mechanisms of inhibition and suggests isoform-selective design strategies.

Gut bacteria utilize dietary and host oligosaccharides for nutrients. Structural and biochemical evidence now demonstrates a conserved catalytic mechanism but diverse substrate preferences for a family of glycoside hydrolases, explaining how they break down complex glycans.

Although rare, small molecules that covalently bind one non-enzyme protein could have important applications—for instance, as imaging and therapeutic agents. A newly designed ligand that selectively binds to transthyretin and reacts chemoselectively with a lysine provides enhanced efficacy over a noncovalent analog in inhibiting amyloid fibril formation.

Differences in packing and solvent exposure of hydrophobic residues determine the interactions with cell membranes and toxicity of different oligomers of the model protein HypF-N.

In vitro evolution of synthetic polymers has been limited by a lack of methods for translating genetic information into synthetic libraries and for amplifying selected molecules. An in vitro selection system for peptide nucleic acids (PNA) now brings the evolution of functional PNA polymers within reach.