Chemical Biology of Natural Products

Book Preface

Chemical biology, biochemistry, and biological chemistry? So what, if anything, are the similarities and differences? One easy definition of the first and last terms would be that Chemical biology = The biology of chemicals, whereas Biological chemistry = The chemistry of biology, and Biochemistry is the study of the chemistry of living systems.

This definition dilemma is further illustrated by the fact that there are eminent universities across the United States where there are chemical biology programs in the College of Chemistry (Berkeley, for example*), but also biochemistry in the same university but housed in the College of Letters and Science†; and at the University of Pennsylvania, the Chemistry Department has a Biological Chemistry Resource Center‡ and a chemical biology postgraduate program,§ with a biochemistry program included within the Medical School.¶ We should add that one of the editors practiced as a biological chemist in the U.S. pharmaceutical industry 45 plus years ago, studying the effect of small synthetic molecules on oxygenation of hemoglobin. Today, he might well have been practicing chemical biology! The Broad Institute, based in Cambridge, Massachusetts,** defines chemical biology as “the science of small molecules in the context of living systems to discover and to elucidate molecular pathways fundamental in cellular, developmental and disease biology.”††

Furthermore, a survey based on leading journals at the interface between chemistry and biology, conducted by the American Chemical Society (ACS), of 4000 scientists working at the interface of chemistry and biology, indicated that natural products did not feature in the top eight disciplines (bioorganic chemistry, medicinal chemistry, molecular biology, enzymology, biophysics, biotechnology, cell biology, and structural biology) selected as being linked to chemical biology.‡‡ Interestingly, when natural products was used as the lead term, the survey selections indicated that they were linked in decreasing order to medicinal chemistry, bioorganic chemistry, chemical biology, plant science, and pharmacology, but not to microbiology.

Attempting to separate the three disciplines mentioned in the first paragraph is probably an exercise in frustration. However, what intrigues us about the Broad Institute definition and the results of the ACS survey discussed above is the apparently widespread lack of appreciation of the role played by natural products in the area of chemical biology. Even more puzzling is the apparent failure to link natural products to microbiology. We therefore decided that a volume highlighting the role of natural products in chemical biology would be an enlightening undertaking and that such a volume should include examples of all three methods of interrogating Mother Nature in individual chapters.

The 15 chapters in this book range over the gamut of the definitions alluded to above and serve to emphasize the dominant role played by microbes in the production of bioactive metabolites. On the chemical biology front, they include the chemical biology of cyanobacteria, combinatorial biosynthesis, including synthetic biology, target identification from natural product inspired structures, and syntheses devised around active natural product structures. Moving to secondary metabolites that may be used in the future to probe biological systems or are themselves the products of complex interactions, there are discussions covering materials from insect–microbe symbioses, compounds from plant–endophytic microbes and rhizosphere interactions, and the coculture of microbes to induce production of fungal metabolites. Also covered are secondary metabolites from extremophilic sources, including toxic lakes and deep-sea sediments and vent organisms, and a chapter covering genomic mining of microbes to find novel bioactive natural products. Finally, moving closer to biological chemistry and/or biochemistry, there are significant discussions of neurotoxins from venomous Conus species and the somewhat similar active cyclic sulfidebridged peptides from plants and animals.