Volume 8 Issue 7, July 2012

The aerial surfaces of land plants are surrounded by cutin, a strong, lipid-based polymer assembled from glycerol and oxidized fatty acids. The first extracellular enzyme forming polyester linkages that are central to the assembly of cutin is now identified.

Modular polyketide synthases are intensively studied as exquisite synthetic machines generating bioactive natural products. The enoylreductase, a common component of these machines, has been structurally and functionally characterized, revealing a new complex architecture.

The proapoptotic cysteine protease caspase-6 participates in the neuropathology of several diseases. Unlike the active dimeric form, the caspase-6 zymogen forms a unique tetramer that can be stabilized by allosteric inhibitors, which prevents caspase-6 activation.

The origin of the flavonoid biosynthetic enzyme chalcone isomerase has remained a mystery. A combination of phylogenetic analysis, crystallography, biochemistry and genetics has uncovered how a stereospecific chalcone isomerase could have evolved from a nonenzymatic ancestral gene.

Mapping of a mutation in a tomato deficient in the plant cuticle component cutin yields the first cutin synthase, as shown via accumulation of polymer precursors and in vitro oligomerization of synthetic substrates.

Many efforts to expand the genetic alphabet and reprogram the genetic code have relied on synthetic DNA nucleotides designed to have pairing properties orthogonal to those of natural base pairs. A structural study shows that DNA polymerases enhance the efficiency of non-natural base pair replication by enforcing a standard Watson-Crick geometry in the polymerase active site.

The first crystal structure and in vitro biochemical characterization of an enoylreductase domain from a multimodular polyketide synthase indicates substantial architectural deviations from the mammalian fatty acid synthase and identifies an active site residue that controls catalytic activity.

BRET probes that monitor activation of multiple G protein isoforms reveal that angiotensin II and a biased agonist of the angiotensin II type 1A receptor stabilize distinct receptor conformations associated with different signaling outputs.

The first small-molecule inhibitor of chemoattractant GPCR OXE-R disrupts signaling downstream of Gβγ but not Gα_i/o, providing evidence that signaling bias can occur between Gβγ and Gα subunits within a heterotrimer.

A computational screen identifies a small-molecule activator of proapoptotic BAX that selectively binds to the BAX trigger site, inducing characteristic conformational changes, oligomerization and BAX-dependent cell death.

A genetic synthetic lethal screen reveals that ATM and MET kinases promote cell survival upon activation of p53 with Nutlin-3, and these survival pathways act in parallel to canonical cell cycle arrest and apoptotic genes induced by p53.

Phage display reveals peptides that bind to the caspase-6 zymogen, inducing its tetramerization and specifically inhibiting its enzyme activity both in vitro and in neuronal cells.

Fluorinated, cell-permeable analogs of sialic acid and fucose are processed by monosaccharide salvage pathways to generate sialyl- and fucosyltransferase inhibitors intracellularly. These compounds serve as important new tools to dissect the role of glycan modifications within complex biological systems.