Chemical Biology Meets Biological Chemistry Minireview Series

What is the difference between “biological chemistry” and “chemical biology?” One of us (J. M. G.) received his Ph.D. at an institution where the biochemistry building was called the Laboratory of Chemical Biology, but that was a long time ago, and things have changed. Biological chemistry (or biochemistry), that is the study of life processes at the molecular level, is now quite distinct from chemical biology. According to Wikipedia, “Chemical biology is a scientific discipline spanning the fields of chemistry and biology that involves the application of chemical techniques and tools, often compounds produced through synthetic chemistry, to the study and manipulation of biological systems.”

Throughout the 105-year history of the Journal of Biological Chemistry, papers using techniques of chemistry to understand biological processes have appeared in the Journal, and in fact, many papers describing the development of chemical reagents and small molecule enzyme inhibitors top the all-time most-cited list of Journal papers (www.jbc.org/reports/most-cited). However, several new journals have now emerged to emphasize the growing importance of chemical biology as a unique discipline, albeit within the bounds of biological chemistry. The following minireviews emphasize the importance of uniting synthetic chemistry with biochemistry toward understanding complex biological processes, in other words, how relevant chemical biology is to biological chemistry. These minireviews highlight both the application of chemical techniques toward understanding life processes at the molecular level (i.e. biochemistry) and the development of synthetic compounds either as tools for research or as candidate therapeutics for human diseases. These topics are naturally within the scope of interest of the Journal.

In the minireview by Lori W. Lee and Anna K. Mapp, “Transcriptional Switches: Chemical Approaches to Gene Regulation,” the authors describe the development of synthetic small molecules to control transcription in eukaryotic cells. These studies underscore both of the approaches described above, namely development of molecules to probe the mechanisms underlying transcriptional regulation and identification of potential drug candidates. Both screening of chemical libraries and rational synthesis based on known protein structures have been used in the development of novel small molecule transcriptional regulators. One example discussed by Lee and Mapp concerns the important transcription factor and tumor suppressor protein p53. About 50% of human cancers involve misregulation of p53, mainly by mutations in the p53 gene. Molecules that disrupt the interactions between this important transcriptional regulatory protein and its protein partners, or molecules that restore normal function to mutant p53, may serve as novel cancer therapeutics. This is just but one example of the exciting potential for small molecule gene regulators in human health.

In their minireview “Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon,” Travis S. Young and Peter G. Schultz describe efforts to introduce non-natural amino acids into proteins. Nature does this in the case of selenocysteine through conversion of serine to selenocysteine, but researchers, through the use of orthogonal aminoacyl-tRNA synthetase/tRNA pairs, have been able to introduce a myriad of unnatural amino acids into recombinant proteins in bacteria, yeast, and mammalian cell lines. Amino acid side chains that contain fluorophores, post-translational modifications (such as acetyllysine and phosphoserine), metal ion-binding ligands, reactive moieties, and photocross-linking reagents, among others, have been successfully and site-specifically incorporated into a host of proteins. These modifications have been a boon to the NMR and x-ray crystallography research communities and have provided valuable probes for protein function within living cells.

Whereas the techniques discussed by Young and Schultz can be applied to study the role of post-translational modifications of the histone proteins (lysine acetylation), in their minireview “Chemical Approaches for Studying Histone Modifications,” Champak Chatterjee and Tom W. Muir describe complementary approaches using techniques of native chemical ligation and related synthetic methods to generate histones with unique post-translational modifications, such as lysine methylation and acetylation. These modifications are known to regulate gene expression, but functional studies have been limited by the availability of uniquely and homogeneously modified histones. Thus, these chemical methods have allowed investigators to probe chromatin structure and function in ways that could not have been achieved with mixed populations of histones isolated from biological sources. These studies have led to the identification of particular lysine residues in histones that mediate internucleosome interactions and chromatin condensation and likely regulate gene expression.

Gabriel M. Simon and Benjamin F. Cravatt describe “Activity-based Proteomics of Enzyme Superfamilies: Serine Hydrolases as a Case Study.” Activity-based protein profiling relies on chemical probes, consisting of a ligand for the enzyme or protein family under study linked to a reactive group for covalent modification of the protein, and a reporter tag to either enrich (such as biotin) or visualize (a dye) and identify the targets of this probe. This technique offers investigators the opportunity to identify the targets of existing small molecules, to characterize members of enzymes families en masse (as in the present example), or to screen for inhibitors. The importance of this work for basic research is underscored by the fact that only a fraction of the predicted proteins in the human genome have actually been characterized and are of known function. Additionally, this approach offers the opportunity to screen for inhibitors, which may lead to potential drugs.

In the minireview “Chemical Inducers of Targeted Protein Degradation,” Kanak Raina and Craig M. Crews describe chemical alternatives to RNA interference strategies to probe the function of selected protein targets in living cells. Common drawbacks to short hairpin RNA and small interfering RNA approaches are off-target effects and the difficulty in dealing with long-lived proteins. To circumvent these limitations, Crews and others have developed methods to target proteins for destruction by the proteasome by targeted linkage of ubiquitin to the protein of interest either through chemical tags or by introducing specific recombinant versions of the protein in cells, which can be degraded in a programmable fashion. Raina and Crews review the many successful applications of this technology.

Finally, in a complementary approach to that described by Raina and Crews, David C. Rubinsztein and co-workers describe “Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases.” Many of the inherited and sporadic neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease and Huntington disease, involve protein aggregation, and small molecules that would effectively remove such mutant proteins would likely be of tremendous therapeutic benefit. To this end, a number of groups have focused on the development of molecules to up-regulate autophagy or the specific clearance of aggregated proteins.

Although we recognize that these minireviews provide only a limited snapshot of the bustling field of chemical biology, the topics were chosen to highlight recent successes in the application of chemical methods to important problems in biology and show how such approaches may even improve human health. We certainly apologize to members of the chemical biology research community whose work could not be covered in this brief minireview series, as space limitations precluded including many important areas of chemical biology research. We hope that these minireviews convey the excitement felt in the research community for the application of chemical methods to important biological problems.