Natural Products as Probes of Cellular Function: Studies of Immunophilins



One of the great mysteries of cell biology remains the mechanism of information transfer, or signaling, through the cytoplasm of the cell. Natural products that inhibit this process offer a unique window into fundamental aspects of cytoplasmic signal transduction, the means by which extracellular molecules influence intracellular events. Thus, natural products chemistry, including organic synthesis, conformational analysis, and methods of structure elucidation, is a powerful tool in the study of cell function. This article traces our understanding of a group of natural products from the finding that they inhibit cytoplasmic signaling to their current recognition as mediators of the interaction between widely distributed protein targets. The emphasis of the discussion is primarily structural. The interactions between the natural-product ligands and their protein receptors are analyzed at a molecular level in order to shed light on the molecular mechanisms of the biological functions of these compounds. In the process we hope to illustrate the power of chemical analysis as applied to biological systems. Through chemistry we can understand the molecular basis of biological phenomena.