Sulfur-containing cofactors participate in a wide range of essential biological reactions. Although sulfur has long been recognized as indispensable to protein cofactors, its incorporation into biomolecules is not completely understood. In most organisms, the recruitment of sulfur for the synthesis of several cofactors involves the participation of a single general enzyme, cysteine desulfurase. The recruitment of such a promiscuous enzyme therefore poses an experimental challenge for dissecting the specific mechanisms of sulfur mobilization because its inactivation affects the synthesis of most sulfur cofactors. Gram-positive microbes such as Bacillus subtilis, on the other hand, code for several distinct cysteine desulfurases. Based on their genomic location, coding sequences, and preliminary analyses, the lab hypothesizes that each has specialized functions in sulfur metabolism. Using a combination of molecular genetics, biochemical and spectroscopic approaches, the lab will investigate the specific catalytic mechanisms by which these enzymes mobilize sulfur and their participation in the biosynthesis of sulfur cofactors using Bacillus subtilis as the model organism. This project will (i) establish the evolutionary importance of the differentiation and specialization of cysteine desulfurases; (ii) define key aspects of their structural, mechanistic, and functional relationships; and (iii) provide an excellent model system to study sulfur-trafficking reactions uncoupled from iron-sulfur metabolism. Successful results will transform our understanding of life-sustaining reactions and the intersections of metabolic pathways in the synthesis of essential sulfur cofactors.
Broader Impact The broader impacts of this CAREER project will include the involvement of graduate students from Wake Forest University and undergraduate students from neighboring institutions in a mentored research/professional development program. The support team comprised of graduate students and instructors will develop a career plan for the students, which will include summer research experience and participation in professional development activities and meetings during the academic year. This program aims to broaden the scientific research preparation and participation of underrepresented groups in science. The team-mentoring approach will also have an impact on participating graduate students and their training as future teacher-scholars.
