Table of contents



Focus on Lipids

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.



Focus on Lipids

Unlocking the lipid labyrinth p471


Progress in understanding the functions of individual lipids has lagged behind that for other bioactive molecules, but recent technologies that enable the monitoring of individual lipids provide hope.



Focus on Lipids

Challenges in studying phospholipid signaling pp473 - 475

Carsten Schultz


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.

Focus on Lipids

Seeing the future of bioactive lipid drug targets pp476 - 479

Jilly F Evans & John H Hutchinson


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.


Research Highlights

Our choices from the recent literature pp480 - 481



News and Views

Drug discovery: Know your chemical space pp482 - 483

Andrew L Hopkins & G Richard Bickerton


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.

See also: Article by Burns et al.

Protein localization: Can too much lipid glue stop Ras? pp483 - 485

Adrienne D Cox


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: Hypothesis-driven omics integration pp485 - 487

Andreas Schmid & Lars M Blank


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.

Lipids: The plasma membrane code pp487 - 488

Anthony H Futerman & Maya Schuldiner


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.


Brief Communication

4-Nitrobenzoate inhibits coenzyme Q biosynthesis in mammalian cell cultures pp515 - 517

Ulrika Forsman, Mats Sjöberg, Mikael Turunen & Pavel J Sindelar


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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.



Marine antifungal theonellamides target 3β-hydroxysterol to activate Rho1 signaling pp519 - 526

Shinichi Nishimura, Yuko Arita, Miyuki Honda, Kunihiko Iwamoto, Akihisa Matsuyama, Atsuko Shirai, Hisashi Kawasaki, Hideaki Kakeya, Toshihide Kobayashi, Shigeki Matsunaga & Minoru Yoshida


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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.

Branched intermediate formation stimulates peptide bond cleavage in protein splicing pp527 - 533

Silvia Frutos, Michael Goger, Baldissera Giovani, David Cowburn & Tom W Muir


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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.

Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes pp534 - 540

Yao-Wen Wu, Lena K Oesterlin, Kui-Thong Tan, Herbert Waldmann, Kirill Alexandrov & Roger S Goody


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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.

Structural basis of G protein–coupled receptor–G protein interactions pp541 - 548

Jianxin Hu, Yan Wang, Xiaohong Zhang, John R Lloyd, Jian Hua Li, Joel Karpiak, Stefano Costanzi & Jürgen Wess


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

A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans pp549 - 557

Andrew R Burns, Iain M Wallace, Jan Wildenhain, Mike Tyers, Guri Giaever, Gary D Bader, Corey Nislow, Sean R Cutler & Peter J Roy


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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.

See also: News and Views by Hopkins & Bickerton