Volume 10 Issue 6, June 2014

The addition of polysialic acid to proteins and cells is emerging as a promising therapeutic strategy. Polysialyltransferases synthesize polymers of widely varying lengths not optimal for therapeutic reagents, but the development of enzyme variants using neutral genetic drift offers a new way to overcome this problem.

The finding that the antifungal activity of amphotericin B is primarily due to its ability to extract ergosterol from fungal membranes suggests a new rationale for drug design, which should lead to advanced treatments, particularly for invasive fungal infections.

Deciphering the molecular basis of HCN channel regulation by cGMP leads to the serendipitous discovery of cyclic dinucleotides as potent inhibitors of I_f current in the heart.

The phytohormone abscisic acid (ABA) has a central role in adaptive responses of plants to abiotic stress. A new ABA antagonist offers a promising tool to study ABA signaling and adaptation to abiotic stress in diverse plants, including crops.

Understanding the mechanisms by which gut metabolites impact host physiology should help understand a variety of disease associated with gut-microbiota dysbiosis. A review of this microbial impact in both invertebrate and vertebrate highlights roles in energy harvest, pathogen resistance and the development of allergic and neurological disorders.

Ether lipids are found in both mammals and bacteria, but only the mammalian biosynthesis pathway is known. Bioinformatic, biochemical and genetic evidence now locate the bacterial pathway within a multigene cluster that includes the four-domain, PKS-like ElbD.

The transplantation of residues from a selective to a nonselective haloalkane dehalogenase yields the correct active site geometry but not function. Computational and biophysical results explain this disparity, showing that the dynamics and hydration of the engineered protein match its parent, not its target.

Directed evolution of the final enzyme in the lovastatin biosynthetic pathway yields a variant with 29 mutations that does not require a carrier protein and displays altered dynamics of the catalytic residues, spending more time in the catalytically active conformation.

Functional assessments and applications of polysaccharides are hampered by broad product distributions. Neutral drift libraries now identify specific amino acids and binding sites that determine product outcome in a polysialyltransferase, allowing the preparation of glycan chains with defined lengths.

In silico screening identifies a small molecule that stabilizes the interaction between retromer components Vps35 and Vps29. The compound increases traffic of APP away from the endosomal compartment to limit generation of the Aβ peptides involved in Alzheimer's disease pathology.

β-Aminobutyric acid (BABA) is a small-molecule activator of plant disease resistance. Binding of (R)-BABA to IBI1—an aspartyl-tRNA synthetase (AspRS)—primes noncanonical defense pathways, resulting in broad-spectrum disease resistance. Ligand binding also blocks AspRS activity, leading to accumulation of aspartic acid and uncharged tRNA, which activate a second plant stress response.

A cyclic dinucleotide binds to a ‘C-linker pocket’ of the HCN4 ion channel, a site that is distinct from the cyclic nucleotide binding site used for channel regulation. A small molecule found to interact with the C-linker pocket can antagonize cAMP regulation of the channel.

Endosomes and lysosomes are electrically excitable, and this is conferred by a new family of atypical voltage-gated sodium channels, lysoNa_Vs, formed by TPC1, which has similar mechanisms for gating as canonical voltage-gated channels and is sensitive to pH, appropriate for its localization in acidic compartments.

An array of approximately 300 different carbohydrate structures from select gut bacteria was generated and probed with mouse and rabbit IgG samples. The binding results indicate that galectins 3, 4 and 8 of the innate immune system can recognize certain microbes only if they express self-like antigens.

Abscisic acid (ABA), a small-molecule hormone that regulates stress responses in plants, initiates signaling by nucleating ABA receptor–PP2C interactions. A structure-guided approach has produced a class of 3′-S-alkylated ABA derivatives that prevent PP2C binding to ABA receptors by blocking a solvent-exposed channel.