Volume 6 Issue 6, June 2010

These highlights showcase papers across the history and scope of Nature Chemical Biology.

Artificial biosynthetic pathways are typically assembled and optimized progressively, from earlier to later steps. This commentary highlights the potential of an alternate regressive method for biochemical pathway design and generation, inspired by the retro-evolution hypothesis and the concept of retrosynthesis. In addition to being a pathway design tool, 'bioretrosynthesis' has potential as a construction and optimization methodology.

Drugs identified in high-content screens are often difficult to link to the cellular target, especially when multiple signaling pathways impinge on the phenotypic endpoint. A chemical-genetic approach in fruit fly cells now greatly improves the prioritization of drug hits by directing the screen toward a single pathway.

The ability to degrade atrazine has been engineered in a strain of Escherichia coli capable of responding specifically to the presence of the herbicide. A chemical biology approach generated an atrazine-sensitive riboswitch enabling a cellular response to occur only in the presence of the toxin.

A new study fulfills a central goal of post-genomic medicine, the treatment of inherited loss-of-function disorders not by correcting a genetic mutation but by augmenting the efficiency with which the nascent mutant gene product undergoes conformational maturation and is deployed to its site of action.

COX-2 is the enzyme largely responsible for causing inflammation, a common mechanism of disease. A study now reports that derivatives generated by COX-2 from naturally occurring ω-3 fatty acids are anti-inflammatory mediators.

Bacterial polysaccharides exhibit remarkable structural diversity and play critical roles in the biology of their producing organisms. A recent study defines the minimal machinery for polymerization in a widely disseminated assembly pathway.

A new NMR method—requiring only milligram quantities of substrates—uses isotopically labeled neighbor atoms to directly and continuously report on KIEs at the reaction center. Application of the methodology defines a reaction coordinate for sialidase hydrolysis.

The chemical synthesis of acylated dipeptide substrates for SfmC, a tetradomain NRPS enzyme, defines the mechanism of formation of two rings in saframycin and explains the unusual presence of a fatty acid loading system in this biosynthetic gene cluster.

Metabolomics analysis of stem cells and differentiated cells points to chemical unsaturation as a key feature of stem cell metabolites. Manipulation of these metabolites' concentrations directly influences stem cell behavior, highlighting biological oxidation as a driver for differentiation.

O-polysaccharide is a major constituent of the bacterial cell wall, yet little mechanistic information is known about its biosynthesis. A reconstruction of this pathway using defined substrates now demonstrates the basis for sugar polymerization and length modulation.

Enhancing calnexin function by increasing the ER calcium concentration resculpts the mutant glucocerebrosidase folding free energy diagram in the ER of Gaucher's disease cells, enhancing folding at the expense of the ER-associated degradation pathway.

Six new species of electrophilic lipids identified in activated macrophages are derived from COX-2 action on ω-3 fatty acids and mediate anti-inflammatory and anti-oxidant activities.

Interaction between HIV-1 integrase and the cellular cofactor LEDGF/p75 is important for viral integration. Newly designed small molecules that block this interaction inhibit HIV replication, illustrating the potential of viral–host protein-protein interaction inhibitors.

Reversible palmitoylation controls the localization and signaling of Ras. Development of a potent and specific small molecule inhibitor of the thioesterase APT1 reveals that this enzyme depalmitoylates Ras in cells. Inhibition of APT1 led to redistribution and altered activity of HRas, NRas and an oncogenic mutant Ras.

A new pathway screen for small molecules that suppress or enhance an RNAi phenotype in Drosophila cells was used to identify a collection of compounds that perturb different steps in the Rho pathway.

Synthetic biology enables the reprogramming of cells for useful applications. RNA selection approaches yielded an atrazine-binding riboswitch that was used to engineer Escherichia coli that migrate toward and catabolize this common herbicide.