Kinases are a large and diverse family of enzymes essential to basic biological functions in cells. Kinases act by adding phosphate groups to protein substrates, which profoundly impacts the ability of the modified substrate to regulate human biology. Kinases that modify serine, threonine, and tyrosine amino acids within protein substrates are extensively studied due to their having clear roles in cell function and dysfunction. Recently, a new family of protein kinases that modify histidine amino acids has emerged as likely players in human cell biology. However, few methods are available to study histidine kinases, due to their unique structure and function. Professor Mary Kay Pflum and her undergraduate and graduate students at Wayne State University aim to apply her pioneering chemical approach of using adenosine triphosphate (ATP) analogs to study histidine kinase enzymes. The new chemical tools developed in this project are critical to fully reveal the chemical role of histidine kinases in cell biology. Integral to the project is the involvement of undergraduate and graduate students. At the middle and high school levels, Professor Pflum introduces students from the Detroit metropolitan area to multidisciplinary science and scientific careers through outreach programs. By integrating research and educational activities, this application broadly impacts the community by fostering the next generation of scientists.
With funding from the Chemistry of Life Process Program in the Division of Chemistry at the NSF, Dr. Mary Kay Pflum of Wayne State University builds on prior work with adenosine triphosphate (ATP) analogs being used to develop kinase-catalyzed labeling of substrates. Given the paucity of chemical tools to study the chemical process of phosphohistidine-mediated cell biology, the overall goal of this project is to apply kinase-catalyzed labeling to human histidine kinases. Dr. Pflum accomplishes this overarching goal by: 1) establishing kinase-catalyzed labeling with human histidine kinases; 2) using kinase-catalyzed labeling to identify phosphohistidine-containing proteins; and 3) creating probes to monitor histidine kinases in human cells. These studies represent a first step toward Dr. Pflum's long-term objective to study the role of phosphohistidine in cellular processes. The identification of new chemical mechanisms in cell biology related to phosphohistidine has wide implications in human biology.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
