With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Indraneel Ghosh from the University of Arizona to develop new methods for controlling the activities of enzymes implicated in posttranslational chemical modifications using a combination of protein engineering and designed small molecules. The biological activity of proteins is controlled by numerous posttranslational modifications, whereby small chemical entities are added to newly synthesized proteins. Almost all enzymes that are responsible for catalyzing posttranslational modifications belong to large families with similar structures. This similarity precludes the design of specific small molecule probes for the direct inhibition or activation of the function of a specific enzyme. A few elegant chemical genetic approaches have been developed to address this need but it remains challenging to control the activity of more than one enzyme within the same family in order to turn-on a desired enzyme to probe biology or engineer new and useful pathways. This proposal seeks to establish a toolbox of enzymes that respond to unique molecular switches. This project at the interface of chemistry and biology will offer a rich training ground for a diverse collection of undergraduate and graduate students. The research will also accelerate the development of multidisciplinary undergraduate courses, with a focus on modern laboratory research methods and cross-disciplinary colloquiums for discussing a number of current topics.
In particular, enzymes involved in acetylation and deacetylation will be redesigned for rendering them amenable to small molecule control. A new and general method for controlling specific enzymes will also be developed using an engineered allosteric switch. New knowledge obtained from the proposed approaches has the potential to provide the community with the ability to target multiple enzymes with unprecedented orthogonal control. These methods have the potential to better decipher the chemical cross-talk that governs biology and aid in the reengineering of cellular pathways with many potential applications.