Volume 9 Issue 2, February 2013

Whole-organism screening is emerging as a promising alternative to cell-based assays, particularly for the study of processes that integrate information across cells and tissues. High-throughput screening of zebrafish larvae has enabled the discovery of small molecules that lower blood glucose levels and alleviate pathological symptoms in a mouse model of obesity and diabetes.

There is a considerable amount of oxidized glutathione in living cells, yet it is virtually absent from the cytosol. The mystery of where it resides has now been solved. A study in baker's yeast revealed that oxidized glutathione is selectively stashed in vacuoles.

Cholic acid and 24(S),25-epoxycholesterol are oxysterols detected in the developing mesencephalic tissue and selectively regulate the production of either the red nucleus or dopaminergic neurons via activation of the liver X receptors.

Metabolites and cofactors can be converted to unwanted compounds by promiscuous enzymes and spontaneous chemical reactions. The growing list of enzymes that correct or prevent these reactions, akin to those that combat DNA and protein damage, have important roles in maintaining homeostasis and preventing disease.

Structural characterization of an artificial zinc-dependent enzyme created by in vitro evolution yields a new, flexible fold that challenges straightforward definitions of active site residues and raises questions about protein evolution.

Bioymifi, a small-molecule death receptor 5 (DR5) agonist, induces selective cancer cell apoptosis as a single agent or in synergy with small-molecule Smac mimetics.

Allosteric conformations and proteolytic activities of each subunit of the trimeric E. coli DegS protease share a cooperatively coupled energy landscape that allows regulation via the binding of substrate and OMP peptides.

Maintaining energy homeostasis requires complex feedback across organs that is difficult to study in isolated systems. New research uses whole-organism screening to identify key regulators of fasting metabolism in zebrafish, including ligands for the mitochondrial transporter protein TSPO.

N⁶-Threonylcarbamoyladenosine (t⁶A), a modified nucleotide found in certain tRNAs, has an essential role in translational fidelity. New analytical data reveal that t⁶A adopts a cyclic form (ct⁶A) in cells and has led to the identification of the enzymes that convert t⁶A to ct⁶A.

An allosteric activator of Hsp70 mimics Hip and reduces neurotoxicity in a model for spinobulbar muscular atrophy by promoting ubiquitination and degradation of oligomeric polyglutamine-containing clients.

Quantification of cytosolic glutathione redox potential leads to the discovery that the ABC-C transporter Ycf1 rapidly transports oxidized glutathione (GSSG) into vacuoles and whole-cell GSSG should not be used as a proxy for cytosolic GSSG.

Cholic acid and 24(S),25-epoxycholesterol are endogenous midbrain LXR ligands that are neurogenic for red nucleus or dopaminergic neurons, respectively.