Focus
1st anniversary highlights
The June 2006 issue represents one year of Nature Chemical Biology. To mark our anniversary, we have compiled some highlights from our first 12 issues. These items, which are free for the month of June 2006, reflect the editorial scope and the diversity of content featured in Nature Chemical Biology. We hope that you will enjoy them and join us in looking forward to our second year of publication of top-tier research and commentary at the interface of chemistry and biology. In the coming months, Nature Chemical Biology will bring you new types of content such as our 'Elements' section and additional thematic issues.
June 2005
Editorial: A community of chemists and biologists
In our view, chemical biology focuses on understanding biological systems at the molecular level and using these mechanistic insights to expand chemistry and biology in new directions. Our primary aim in launching Nature Chemical Biology was to create a top-tier international journal to reflect the diversity and excitement of chemical biology research. We strive to reach out to the chemistry and biology communities equally and deliver monthly issues that will spur interactions between these traditional disciplines.
Review: Chemistry in living systems
Jennifer A Prescher and Carolyn R Bertozzi
Green fluorescent protein is a powerful label for cellular imaging of proteins, but it cannot be easily extended to other biomolecules. In their Review, Prescher and Bertozzi describe the recent development of bioorthogonal chemical reporters as an alternative for tagging biomolecules. In this approach, a small label, with chemical reactivity distinct from that of biologically occurring molecules, is attached to the desired biomolecule by cellular machinery and detected by selective reaction with a probe.
July 2005
Article: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Alexei Degterev, Zhihong Huang, Michael Boyce, Yaqiao Li, Prakash Jagtap, Noboru Mizushima, Gregory D Cuny, Timothy J Mitchison, Michael A Moskowitz and Junying Yuan
There are two major forms of cell death, apoptosis and necrosis. Using high-throughput screening, Yuan and colleagues identified necrostatin-1, a chemical inhibitor of death receptor-induced necrotic cell death. Necrostatin-1 specifically blocked necrotic cell death but not apoptosis. So, much like apoptosis, necrosis can be triggered by precise cellular pathways. The authors found that this pathway, which they named necroptosis, has an important role in a mouse model of ischemic brain injury.
August 2005
Letter: High-throughput assays for promiscuous inhibitors
Brian Y Feng, Anang Shelat, Thompson N Doman, R Kip Guy and Brian K Shoichet
Shoichet, Guy and colleagues report that a surprisingly large percentage of 1,000 'drug-like' small molecule inhibitors showed nonspecific or promiscuous inhibition in enzyme assays. The authors developed rapid assays that enabled identification of these non-specific inhibitors that are prone to aggregation. They also used this information to refine a computational program for identification of promiscuous inhibitors. The combination of these biochemical assays and in silico methods provides an opportunity to more efficiently identify drug lead candidates.
News & Views: New screening tools for lead compound identification
Tomi K Sawyer
September 2005
Article: Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids
Bethany A Janowski, Kunihiro Kaihatsu, Kenneth E Huffman, Jacob C Schwartz, Rosalyn Ram, Daniel Hardy, Carole R Mendelson and David R Corey
Article: Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs
Bethany A Janowski, Kenneth E Huffman, Jacob C Schwartz, Rosalyn Ram, Daniel Hardy, David S Shames, John D Minna and David R Corey
Two papers by Corey and coworkers achieved gene inhibition by targeting DNA transcriptional start sites with complementary sequences of antigene protein nucleic acids (agPNAs) and antigene RNAs (agRNAs). agPNA and agRNA sequences designed to bind the transcriptional start site of the human progesterone receptor (hPR) were both potent inhibitors of hPR mRNA production. The authors also demonstrated that agRNA sequences that targeted the transcriptional start sites of three different genes led to potent gene silencing in cells. These studies showed that the transcriptional start site of genes is a viable target for the inhibition of gene expression in cells, thus offering a complementary method to RNA interference.
October 2005
Letter: Discovery of a new peptide natural product by Streptomyces coelicolor genome mining
Sylvie Lautru, Robert J Deeth, Lianne M Bailey and Gregory L Challis
The isolation of natural products can be laborious and time consuming. Challis and coworkers use a genome mining strategy to identify gene clusters involved in non-ribosomal peptide synthesis. This led the authors to predict the existence of a previously unknown iron-binding siderophore in Streptomyces coelicolor. The new natural tetrapeptide, coelichelin, was isolated under iron deficient conditions. Further detective work revealed that coelichelin is biosynthesized by three non-ribosomal peptide synthetase modules that cooperate with a separate thioesterase domain. This study highlights genome mining as an alternative route to the identification of new compounds of biological origin.
Book Review: The protein modification repertoire
Reviewed by: Wilfred A van der Donk
November 2005
Letter: Mixture of new sulfated steroids functions as a migratory pheromone in the sea lamprey
Peter W Sorensen, Jared M Fine, Vadims Dvornikovs, Christopher S Jeffrey, Feng Shao, Jizhou Wang, Lance A Vrieze, Kari R Anderson and Thomas R Hoye
The sea lamprey (Petromyzon marinus) is an ancient parasitic fish that survives by sucking the bodily juices out of larger fish. Sorensen, Hoye and coworkers report the identification and structural characterization of a mixture of steroid-like compounds that are secreted by lamprey larvae and that attract adult fish to spawning areas. The team showed that three compounds secreted from larvae contain a steroid scaffold but are modified with sulfate and unusual amino groups. Under appropriate conditions, the pheromone mixture is a potent signal to direct the migrating adult sea lampreys. The identification of this class of sea lamprey pheromones provides new chemical inspiration for managing the ecological problem created by the invading sea lamprey.
Meeting Report: Programming cellular function
Christopher A Voigt and Jay D Keasling
December 2005
Perspective: Photochemical tools for remote control of ion channels in excitable cells
Richard H Kramer, James J Chambers and Dirk Trauner
Light activation provides a way to temporally and spatially control of biological processes. However, naturally occurring mammalian ion channels cannot be directly activated by light. A number of chemical strategies have now been developed for creating photosensitive ion channels. In a Perspective, Kramer and colleagues review the progress and challenges of different approaches to regulating channel activity with light. These methods offer powerful systems with which to investigate neuronal function.
January 2006
Commentary: The origins of chemical biology
Kim L Morrison and Gregory A Weiss
Brief Communication: Purmorphamine activates the Hedgehog pathway by targeting Smoothened
Surajit Sinha and James K Chen
A purine derivative called purmorphamine induces the differentiation of progenitor stem cells to osteoblasts, or bone-producing cells. Sinha and Chen have now shown that purmorphamine is an agonist of Smoothened. Smoothened is a transmembrane protein that transmits an intracellular signal following Hedgehog binding to its receptor. The authors show that Smoothened is regulated by direct binding of purmorphamine to the transmembrane region. Identification of the target is an important step forward for using this compound as a drug lead for stem cell and cancer diseases in which Hedgehog signaling is misregulated.
February 2006
Article: Ever-fluctuating single enzyme molecules: Michaelis-Menten equation revisited
Brian P English, Wei Min, Antoine M van Oijen, Kang Taek Lee, Guobin Luo, Hongye Sun, Binny J Cherayil, S C Kou and X Sunney Xie
The Michaelis-Menten equation, first reported in 1913, has become an indispensable formalism for understanding enzyme kinetics. Traditionally, Michaelis-Menten kinetics has been measured in 'bulk' solution. Xie and co-workers visualized enzymatic turnover of immobilized β-galactosidase using single-molecule fluorescence microscopy to demonstrate that, over time, the behavior of each molecule recapitulates Michaelis-Menten kinetics. However, for individual enzymes under high concentrations of substrate, enzyme activity showed a 'memory effect', which was attributed to conformational heterogeneity among individual molecules. The study suggests that conformational variations among individual enzymes could be important in cells, where only a few copies of each enzyme may be present.
March 2006
Article: A functional genomics approach to the mode of action of apratoxin A
Hendrik Luesch, Sumit K Chanda, R Marina Raya, Paul D DeJesus, Anthony P Orth, John R Walker, Juan Carlos Izpisúa Belmonte and Peter G Schultz
Apratoxin A, a natural product isolated from marine cyanobacteria, has been shown to have anti-tumor activity. Schultz, Luesch and coworkers found that apratoxin A induced cell-cycle arrest and apoptosis. Using functional genomics approaches, they found that increased FGFR signaling could reduce the effects of the small molecule. Apratoxin A was then found to inhibit a key phosphorylation of STAT3, a downstream effector of FGFR signaling. In agreement with these results, apratoxin A inhibited FGF signaling in vitro and in vivo. STAT3 is known to be activated in a number of cancers, so apratoxin A may provide a therapeutic lead.
April 2006
Letter: Noble metals strip peptides from class II MHC proteins
Stephen L De Wall, Corrie Painter, Jennifer D Stone, Rajintha Bandaranayake, Don C Wiley, Timothy J Mitchison, Lawrence J Stern and Brian S DeDecker
In the immune system, class II major histocompatibility complex (MHC) proteins display peptides on antigen-presenting cells (APCs) for recognition by T cells. DeDecker and colleagues conducted high-throughput screening and found that the Pt(II) complexes cisplatin and carboplatin, as well as Pd(II) and Au(III) complexes, allosterically inhibited peptide-MHC interactions—even those of high affinity. The metal complexes could block APC activation of T cells in vivo. Being able to disrupt peptide-MHC interactions, along with the known in vivo oxidation of Au(I) to Au(III), may now provide a molecular basis for some of the known therapeutic effects of gold compounds.
May 2006
Article: Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish
Peter E Bayliss, Kimberly L Bellavance, Geoffrey G Whitehead, Joshua M Abrams, Sandrine Aegerter, Heather S Robbins, Douglas B Cowan, Mark T Keating, Terence O'Reilly, Jeanette M Wood, Thomas M Roberts and Joanne Chan
Angiogenesis, the process of blood vessel growth, is hyperactivated in certain cancers and is a favorite target for new cancer chemotherapies. Chan and co-workers have developed a regenerative angiogenesis assay in the tailfin of adult zebrafish. They demonstrated that PTK787, a kinase inhibitor, could regulate angiogenesis in the adult caudal fin and that endothelial growth VEGFR signaling was required. Regenerative growth of bone and tissue was unaffected by the chemical inhibition of angiogenesis. Their genetic approach provides a method for the rapid identification of anti-angiogenic lead compounds and a new route to discover genes and molecular pathways involved in angiogenesis.