Volume 6 Issue 7, July 2010

Because of the large number of phospholipids, their highly active metabolism and our lack of understanding of protein-lipid specificity, lipid signaling is a particularly challenging subject to study. Help might come from new tools that will allow us to follow and manipulate lipids and lipid-binding proteins in living cells.

Bioactive lipid signaling allows individual cells within the body to 'see' the surrounding environment and to respond in ways that will benefit the whole organism. Successful drug development for bioactive lipid targets requires a deep knowledge of the biology and pathobiology of each specific lipid signaling pathway.

The susceptibility of organisms to chemical perturbation differs as a result of defenses that limit the permeation of small molecules. Screening for permeation, rather than bioactivity, to identify a priori organism-specific chemical space offers an intriguing approach to phenotypic assays and potentially addresses some fundamental challenges in drug discovery.

The kinetics of the acylation, deacylation and reacylation cycle are important for localization and function of Ras as well as other key signaling proteins. A new small-molecule inhibitor may put the brakes on Ras by inhibiting the deacylation enzyme APT1.

Systems biology methods accumulate a vast array of information to generate hypotheses and discover new cellular relationships. A combination of 'omics' technologies now provides important proof of biochemical predictions and creates new opportunities for understanding cellular functional architecture.

Epistatic maps are used to delineate the modes of interaction of genes in various cellular pathways. A new epistatic map of nearly 400 genes involved in plasma membrane biology has revealed unexpected modes of regulation of endocytosis and sphingolipid metabolism.

Coenzyme Q serves a number of important roles in cells, including as an electron shuttle and as an antioxidant, but the exact roles and specific details of these processes have been difficult to investigate. The discovery of a selective inhibitor for Coq2, a critical enzyme in the biosynthesis of coenzyme Q, now primes the field for new investigations.

The target of theonellamides, a family of bicyclic peptides with antifungal activity, has previously proven elusive. A combination of chemical-genomic profiling and biochemical and cellular analysis now reveals that these compounds target sterols to activate Rho1 signaling and induce membrane damage.

Intein splicing occurs in four steps, but the mechanisms controlling these steps — and thus preventing aberrant splicing — are unknown. Kinetic and NMR analysis of several complex constructs now identifies the rate limiting step as well as the conformational trigger that catalyzes this transformation.

Semisynthetic versions of the small G protein Rab7 in the GDP-bound form have 1,000-fold higher affinity for regulators REP1 and RabGDI because of faster dissociation rates from Rab7-GTP, directly linking nucleotide exchange to Rab membrane targeting.

Crosslinks between the active and inactive M3R and the G-protein G_q to which it couples reveal GPCR-G protein movements that can occur upon agonist binding and define basic architectural features of the interface.

Chemical screening in C. elegans is limited by the relatively poor target accessibility of small molecules. A systematic survey of drug-like small molecule accumulation and metabolism in C. elegans was used to create a computational tool for preselecting compounds likely to effectively perturb worms.

This themed issue features a collection of articles that describe our current understanding of the functions of lipids and the chemical methods used to study them at the individual level and within the larger biological systems where they function.