Articles in 2010

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.

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.

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.

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.

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.

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.

Small RNAs targeted to gene promoters are known regulators of transcription in mammalian cells. Antigene RNAs complementary to non-coding transcripts localized to the 3′ termini of genes are now shown to regulate transcription across long genomic sequences.

The lipocalin protein Scn-Ngal is known to bind iron-chelating siderophores, leading to inhibition of bacterial growth. New results reveal that Scn-Ngal, in the absence of bacterial infection, can form a complex with catechol that binds and transports iron in vivo.

Amide bonds are routinely formed in biological systems using carboxylic acids that have been activated at the expense of ATP. The biochemical characterization of a putative β-lactamase now reveals a new way to form amide bonds using stable methyl ester intermediates.

MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.

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.

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.

A new study fulfills a central goal of post-genomic medicine, the treatment of inherited loss-of-function disorders not by correcting a genetic mutation but by augmenting the efficiency with which the nascent mutant gene product undergoes conformational maturation and is deployed to its site of action.

Bacterial polysaccharides exhibit remarkable structural diversity and play critical roles in the biology of their producing organisms. A recent study defines the minimal machinery for polymerization in a widely disseminated assembly pathway.

The ability to degrade atrazine has been engineered in a strain of Escherichia coli capable of responding specifically to the presence of the herbicide. A chemical biology approach generated an atrazine-sensitive riboswitch enabling a cellular response to occur only in the presence of the toxin.