News & Views in 2009

Protein prenylation plays a key role in the localization and function of many proteins, but the number and identities of prenylated proteins are unknown. A new study uses a multidisciplinary approach to provide a broad yet detailed snapshot of prenylation within the mammalian proteome.

The development of an autocatalytic, exponential replicator that is based solely on nucleic acids has implications for our understanding of the origins of life and potential applications in nucleic acid engineering.

By converting prolyl to 4-hydroxyprolyl residues, prolyl hydroxylases induce a conformational bias into proteins. This conformational preference is a result of a stereoelectronic gauche effect and is crucial for protein-protein recognition in oxygen sensing.

It is well known that HIV-1 deceives the host immune system and usurps host cell machinery to replicate, but it is not known how this viral particle is released from the cell. A recent glycan profiling technique revealed that the glycome signatures of HIV-1 and host cell microvesicles are almost identical, providing important support for the 'exosome' hypothesis of viral release.

Inhibition of growth stimulatory pathways has emerged as a major focus of targeted cancer drug development. New insights regarding potent, transient inhibition of cell signaling may challenge the dogma of medicinal chemistry and clinical trial design.

Newly synthesized secretory and membrane proteins contain cleavable signal sequences at the N terminus that allow for cotranslational protein targeting by interaction with the signal recognition particle (SRP). New results now suggest that signal sequences enable the conserved SRP RNA to accelerate complex formation with the SRP receptor.

Exposure to zinc can cause pain and inflammation and can be harmful to human health. New evidence suggests that activation of the irritant receptor, TRPA1, which is expressed on pain-sensing neurons, may be responsible for some of these symptoms of zinc toxicity.

Under iron-depleted conditions, bacteria produce siderophores that bind iron and are then actively taken up by the cell. New structural and biochemical insights are reported for the synthetic pathway of achromobactin, a siderophore from the plant pathogen Pectobacterium chrysanthemi.

Engineered biosynthesis of modified natural products normally uses microbes as biochemical factories. Now, chemical biologists are taking advantage of the largely untapped biochemical potential of plants.

Rotaviruses have been designated as 'sialidase sensitive' or 'sialidase insensitive', based on how their entry into cells is affected by treating cells with sialidases. A new study uses multiple methods, including saturation transfer difference NMR spectroscopy, to elucidate interesting interactions involving terminal and internal sialic acid moieties, concluding that 'sialidase insensitive' does not mean 'sialic acid independent'.

The 'RNA World' hypothesis presupposes the existence of a catalytic RNA that can polymerize nucleotide triphosphates to replicate a template, but such chemistry has not previously been detected in natural ribozymes. Detailed investigation of the products of a bacterial self-splicing group I intron now suggest that such ribozymes indeed exist in nature.

Access to new analogs of the tetracycline family of antibiotics has thus far been limited to compounds that can be prepared by modification of the isolable natural products. An efficient total-synthesis pathway with extraordinary flexibility has now made it possible to identify new tetracycline derivatives with activity against a wide range of antibiotic-resistant bacteria.

Monomeric fluorescent proteins that change their emission characteristics as they mature have been successfully used to study the spatial and temporal dynamics of lysosome-associated membrane protein type 2A. This methodology provides a new means of studying cellular events in a dynamic mode.

Wnt signals are seemingly ubiquitous in biology, controlling processes as diverse as bristle patterning in flies and tissue regeneration in humans. A new report describes the discovery of small molecules that inhibit Wnt signaling by two unprecedented mechanisms, paving the way for fundamental studies and perhaps improved treatment of colon cancer.

Syntheses of natural product–like compound libraries with high scaffold diversity have proven hard to develop. A strategy employing metathesis cascades to 'zip up' a set of unsaturated building blocks differently connected by variable linkers demonstrates that over 80 distinct scaffold classes can be synthesized in one go.

A powerful technology called global protein stability profiling allows rates of protein turnover to be determined for a substantial fraction of the human proteome in a single experiment. This approach sets the stage for systems-level analyses of the dynamics of the mammalian proteome.

Cytochrome P450 enzymes selectively oxidize relatively unactivated sites in a range of model drug-like substrates in vitro. The hydroxylated products can be transformed into selectively fluorinated systems, providing a rapid sequential method for the identification, activation and fluorination of saturated sites in drug candidates.