Volume 10 Issue 4, April 2014

Coenzyme Q₁₀ is an essential lipid in aerobic respiratory metabolism and a membrane antioxidant. A new function is revealed for CoQ; as a membrane-stabilizing agent that enhances resistance of bacterial cell and liposome membranes to salt stress.

An inhibitor of the deubiquitinase complex USP1-UAF1 highlights the requirement for reversible ubiquitination in DNA repair pathways that are critical for human development and disease.

Probe molecules with systemic activity remain rare, and, as was realized in the pre-molecular era, even their off-target activity can illuminate biology. A study reporting a screen of over 600 kinase inhibitors found nine with bromodomain inhibitory activity and has implications for mechanism and compound optimization.

Metabolically engineered cells are yielding an expansion of specialty chemicals that rival or supplement traditional petroleum-derived chemicals. New results establish a biosynthetic route to volatile esters and larger acetate esters equivalent in size to biodiesel, providing an intriguing new direction to create fragrances, chemicals or fuels.

Heparin analogs can serve as potent anticoagulants, but heterogeneous structures in some preparations and lack of antidote for others can complicate treatments. A chemoenzymatic method that prevents reversible epimerization now enables reversible application of defined constructs in cells and mice.

Synthetic analogs of nocardicin G—a key precursor of β-lactam antibiotics—are used to show that construction of this enigmatic modified tripeptide relies on an unusual thioesterase domain that epimerizes one residue of an intermediate pentapeptide, but only when the lactam ring is already formed.

The use of CoA thioester intermediates drives formation of small- and medium-sized esters in metabolically engineered E. coli cells, including doubly branched chains generated with enzymes from amino acid degradation pathways.

A nontargeted metabolomics approach finds that ubiquinone (Q8) accumulates in E. coli with sustained hyperosmotic stress. A new role for Q8 in stress tolerance does not involve its known roles in radical scavenging or as a respiratory electron carrier.

A tethered ligand approach reveals that four ligand molecules are required for full desensitization of tetrameric iGluR (glutamate receptor) channels. When fewer ligands are bound, which might be the case during synaptic transmission, desensitization is incomplete or non-existent.

Nematodes are known to stand on their tails and wave—a process called nictation—in an effort to find a new host. Studies of Pristionchus pacificus now show these worms can aggregate to nictate collectively, mediated by the newly discovered natural lipid, nematoil.

A coupled activation-dimerization approach to dissect which of the diverse signaling pathways downstream of Src kinase are responsible for its range of functions such as cell spreading and filopodia formation reveals different roles for focal adhesion kinase and p130Cas.

Oligonucleotide-based RNA targeting is facilitated by base pairing rules, but identifying small molecules that uniquely bind a specific RNA sequence has been challenging. Inforna, an RNA sequence–based lead optimization strategy, was developed and applied to identify small molecules that inhibit pre-microRNA processing.

Deubiquitinases (DUBs) are peptidases that remove ubiquitin from post-translationally modified proteins. The identification of a selective small-molecule inhibitor of the USP1–UAF1 deubiquitination complex reveals a role for deubiquitination in regulating the DNA damage response.

Kinases are a widely targeted enzyme class in cancer chemotherapy. Several clinically used kinase inhibitors also inhibit bromodomains, epigenetic ‘readers’ of acetylated lysine residues, suggesting that kinase-bromodomain polypharmacology may offer benefits in therapeutic settings.

XPB and XPD are essential helicases with roles in transcription and DNA repair. Genomewide ChIP analysis revealed that XPB and XPD localize to DNA G-quadruplex sequences, including many at the transcriptional start sites of actively expressed genes, suggesting that these alternative DNA structures may serve as genome regulatory elements.