Volume 7 Issue 11, November 2011

For years scientists have debated whether glycans, like DNA, RNA and proteins, have a true sequence. In a recent study, researchers show that the proteoglycan bikunin has a defined and predictable sequence, opening the door for a new understanding of the glycome.

Crystal structure and drug pharmacophore structure-activity data guided a combined mutagenesis and chemical screen to develop ligand-gated ion channels activated by unique chemical agonists. Through genetic engineering, these channels can be used to manipulate neuronal excitability and dissect the neuronal circuitry responsible for complex behaviors.

The first selective inhibitor of monogalactosyldiacylglycerol (MGDG) synthase was identified from a chemical library screen. The competitive inhibitor effectively targets MGDG concentrations across plant tissues and was used to demonstrate a new role for galactolipids in pollen-tube development.

An untargeted metabolomics approach identifies C14 phosphatidylcholines (PCs) as specific cellular medium-chain substrates of the lipase ABHD3, as well as C5–C8 short-chain PCs including oxidized pro-atherosclerotic and pro-apoptotic PC phospholipids.

Histidine kinase 4 from Arabidopsis thaliana (AHK4) is a membrane-bound receptor for cytokinins, a class of plant hormones involved in growth, development and defense. Crystal structures of the AHK4 sensor domain in complex with various natural and synthetic cytokinins reveal important features of ligand recognition by this cytokinin receptor.

A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities.

Nonsense suppression, or reassigning stop codons to encode for other amino acids, offers a method for expanding the genetic code of proteins. Deletion of release factor 1 in an Escherichia coli strain enables the incorporation of non-natural amino acids into proteins at multiple sites.

A chemical-genetic study predicts mechanisms of resistance to PI3K inhibitors. Activation of NOTCH signaling, which leads to c-MYC expression, can overcome cancer cell dependency on PI3K signaling for growth. NOTCH and PI3K have not previously been linked in breast cancer.

Peptidic natural products are theoretically amenable to characterization by mass spectrometry, but proteomics programs are not trained to discover these compounds. A new strategy uses mass spectrometry and bioinformatics iteratively to rapidly identify both ribosomal and nonribosomal sequences, yielding multiple new compounds.

Rapid reversible inhibitors of the oxygenation activity of COX-2, including ibuprofen and naproxen, selectively inhibit the enzyme with endocannabinoid 2-AG substrates but not with arachidonic acid, and this substrate-selective inhibition may be important for the analgesic activity of the drugs.

A single trimethylated species is obtained in an on-resin N-methylation reaction of a cyclic hexapeptide. This regioselectivity is driven by conformation and the presence of intramolecular hydrogen bonds, and is correlated with membrane permeability of the peptides.

The inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes. Affinity purification using PU-H71 reveals cancer-specific protein networks in chronic myeloid leukemia and that the abundance of tumor-specific Hsp90 clients in cells can predict sensitivity to Hsp90 inhibitors.

Complex polysaccharides are generally thought not to have a defined carbohydrate sequence because their synthesis is not template-directed. Detailed mass spectrometry of bikunin now counters this dogma, showing that each molecular weight species consists of only a single sequence.

Mono- and digalactosyldiacylglycerols (MGDGs and DGDGs) are glycolipids that are central to plant metabolism and photosynthetic membrane biogenesis. Galvestine-1, a small molecule inhibitor of MGDG synthases that was identified in a high-throughput chemical screen in Arabidopsis thaliana, reveals a new role for these galactolipids in pollen-tube development.

Investigations into kanamycin biosynthesis and identification of new pathway intermediates surprisingly point to the substrate specificity of two glycosyltransferases as controlling flux into parallel pathways, allowing changes to product profiles and structures by varying these gatekeeper enzymes.