MINIREVIEW PROLOGUE This paper is available online at www.jbc.org THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 285, NO. 15, pp. 11031–11032, April 9, 2010 © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

Chemical Biology Meets Biological Chemistry Minireview Series* Published, JBC Papers in Press, February 10, 2010, DOI 10.1074/jbc.R110.113126 Benjamin F. Cravatt‡ and Joel M. Gottesfeld§1 From the Departments of ‡Chemical Physiology and §Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

What is the difference between “biological chemistry” and transcriptional regulatory protein and its protein partners, or “chemical biology?” One of us (J. M. G.) received his Ph.D. at an molecules that restore normal function to mutant p53, may institution where the biochemistry building was called the Lab- serve as novel cancer therapeutics. This is just but one example oratory of Chemical Biology, but that was a long time ago, and of the exciting potential for small molecule gene regulators in things have changed. Biological chemistry (or biochemistry), human health. that is the study of life processes at the molecular level, is now In their minireview “Beyond the Canonical 20 Amino Acids: quite distinct from chemical biology. According to Wikipedia, Expanding the Genetic Lexicon,” Travis S. Young and Peter G. “Chemical biology is a scientific discipline spanning the fields of Schultz describe efforts to introduce non-natural amino acids chemistry and biology that involves the application of chemical into proteins. Nature does this in the case of selenocysteine techniques and tools, often compounds produced through syn- through conversion of serine to selenocysteine, but researchers, thetic chemistry, to the study and manipulation of biological through the use of orthogonal aminoacyl-tRNA synthetase/ systems.” tRNA pairs, have been able to introduce a myriad of unnatural Throughout the 105-year history of the Journal of Biological amino acids into recombinant proteins in bacteria, yeast, and Chemistry, papers using techniques of chemistry to understand mammalian cell lines. Amino acid side chains that contain fluo- biological processes have appeared in the Journal, and in fact, rophores, post-translational modifications (such as acetyll- many papers describing the development of chemical reagents ysine and phosphoserine), metal ion-binding ligands, reactive and small molecule enzyme inhibitors top the all-time most- moieties, and photocross-linking reagents, among others, have cited list of Journal papers (www.jbc.org/reports/most-cited). been successfully and site-specifically incorporated into a host However, several new journals have now emerged to emphasize of proteins. These modifications have been a boon to the NMR the growing importance of chemical biology as a unique disci- and x-ray crystallography research communities and have pro- pline, albeit within the bounds of biological chemistry. The fol- vided valuable probes for protein function within living cells. lowing minireviews emphasize the importance of uniting syn- Whereas the techniques discussed by Young and Schultz can thetic chemistry with biochemistry toward understanding be applied to study the role of post-translational modifications complex biological processes, in other words, how relevant of the histone proteins (lysine acetylation), in their minireview chemical biology is to biological chemistry. These minireviews “Chemical Approaches for Studying Histone Modifications,” highlight both the application of chemical techniques toward Champak Chatterjee and Tom W. Muir describe complemen- understanding life processes at the molecular level (i.e. bio- tary approaches using techniques of native chemical ligation chemistry) and the development of synthetic compounds either and related synthetic methods to generate histones with unique as tools for research or as candidate therapeutics for human post-translational modifications, such as lysine methylation diseases. These topics are naturally within the scope of interest and acetylation. These modifications are known to regulate of the Journal. gene expression, but functional studies have been limited by the In the minireview by Lori W. Lee and Anna K. Mapp, “Tran- availability of uniquely and homogeneously modified histones. scriptional Switches: Chemical Approaches to Gene Regula- Thus, these chemical methods have allowed investigators to tion,” the authors describe the development of synthetic small probe chromatin structure and function in ways that could not molecules to control transcription in eukaryotic cells. These have been achieved with mixed populations of histones isolated studies underscore both of the approaches described above, from biological sources. These studies have led to the identifi- namely development of molecules to probe the mechanisms cation of particular lysine residues in histones that mediate underlying transcriptional regulation and identification of internucleosome interactions and chromatin condensation and potential drug candidates. Both screening of chemical libraries likely regulate gene expression. and rational synthesis based on known protein structures have Gabriel M. Simon and Benjamin F. Cravatt describe been used in the development of novel small molecule tran- “Activity-based Proteomics of Enzyme Superfamilies: Serine scriptional regulators. One example discussed by Lee and Mapp Hydrolases as a Case Study.” Activity-based protein profiling concerns the important transcription factor and tumor sup- relies on chemical probes, consisting of a ligand for the enzyme pressor protein p53. About 50% of human cancers involve mis- or protein family under study linked to a reactive group for regulation of p53, mainly by mutations in the p53 gene. Mole- covalent modification of the protein, and a reporter tag to cules that disrupt the interactions between this important either enrich (such as biotin) or visualize (a dye) and identify the targets of this probe. This technique offers investigators * This minireview will be reprinted in the 2010 Minireview Compendium, the opportunity to identify the targets of existing small mol- which will be available in January, 2011. 1 To whom correspondence should be addressed. E-mail: jgottesfeld@ ecules, to characterize members of enzymes families en asbmb.orb. masse (as in the present example), or to screen for inhibitors.

APRIL 9, 2010•VOLUME 285•NUMBER 15 JOURNAL OF BIOLOGICAL CHEMISTRY 11031 MINIREVIEW: Chemical Biology Meets Biological Chemistry

The importance of this work for basic research is under- describe “Chemical Inducers of Autophagy That Enhance the scored by the fact that only a fraction of the predicted pro- Clearance of Mutant Proteins in Neurodegenerative Diseases.” teins in the human genome have actually been characterized Many of the inherited and sporadic neurodegenerative dis- and are of known function. Additionally, this approach eases, such as amyotrophic lateral sclerosis, Alzheimer disease, offers the opportunity to screen for inhibitors, which may Parkinson disease and Huntington disease, involve protein lead to potential drugs. aggregation, and small molecules that would effectively remove In the minireview “Chemical Inducers of Targeted Protein such mutant proteins would likely be of tremendous therapeu- Degradation,” Kanak Raina and Craig M. Crews describe chem- tic benefit. To this end, a number of groups have focused on the ical alternatives to RNA interference strategies to probe the development of molecules to up-regulate autophagy or the spe- function of selected protein targets in living cells. Common cific clearance of aggregated proteins. drawbacks to short hairpin RNA and small interfering RNA Although we recognize that these minireviews provide only a approaches are off-target effects and the difficulty in dealing limited snapshot of the bustling field of chemical biology, the with long-lived proteins. To circumvent these limitations, topics were chosen to highlight recent successes in the applica- Crews and others have developed methods to target proteins tion of chemical methods to important problems in biology and for destruction by the proteasome by targeted linkage of ubiq- show how such approaches may even improve human health. uitin to the protein of interest either through chemical tags or We certainly apologize to members of the chemical biology by introducing specific recombinant versions of the protein in research community whose work could not be covered in this cells, which can be degraded in a programmable fashion. Raina brief minireview series, as space limitations precluded includ- and Crews review the many successful applications of this ing many important areas of chemical biology research. We technology. hope that these minireviews convey the excitement felt in the Finally, in a complementary approach to that described by research community for the application of chemical methods to Raina and Crews, David C. Rubinsztein and co-workers important biological problems.

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