Professor Patricia Dos Santos was recently awarded an NSF grant for her research on “redox reactions in the biosynthesis of thio-cofactors in bacteria”. This project will engage graduate and undergraduate students in the identification physiological reductants participating in the biological synthesis of vitamins and cofactors in bacteria.
Vitamins and other small molecules defined as cofactors that contain sulfur in their chemical structures are widely distributed in nature and essential for life on Earth. All known living organisms use at least a subset of these cofactors in various aspects of metabolism. While their importance in sustaining basic biochemical reactions is widely recognized, the mechanisms of sulfur activation, trafficking, and insertion into cofactors remain not fully understood. It is widely recognized, however, that the free amino acid cysteine is the source of sulfur for the biosynthesis of most sulfur-containing cofactors in bacteria, eukaryotes, and some species of archaea. A family of enzymes named cysteine desulfurases catalyze the first step in sulfur activation. This project will determine the effect of physiological reducing agents -specifically, thioredoxins and small molecules that contain sulfur (glutathione, bacillithiol, and mycothiol)- in biosynthetic reactions and identify specific protein interactions controlling the reactivity of cysteine desulfurases and their sulfur acceptors. This project will broaden the participation of underrepresented groups by including undergraduate researchers from Salem College and Guilford College, two smaller, local, primarily undergraduate institutions. Graduate students serving as co-mentors will gain improved communication skills in preparation as future independent teacher-scholars.
The reaction catalyzed by cysteine desulfurases involves the formation and transfer of a persulfide intermediate to acceptor molecules involved in the biosynthesis of Fe-S clusters, thionucleosides in tRNA, rRNA and DNA, biotin, lipoic acid, molybdenum cofactor, and thiamine. Studying sulfur-transfer reactions in the biosynthesis of thio-cofactors is challenging. One of the major challenges is that sulfur-acceptor proteins are often shared across multiple biosynthetic pathways. This project will determine the involvement of physiological reductants in promoting redox reactions in the biosynthesis of thio-cofactors in bacteria by investigating different cysteine desulfurases that are involved in distinct pathways. The outcome of this study will provide fundamental knowledge regarding the role of redox agents in biochemical pathways involved in the transfer of sulfur and will establish evolutionary determinants controlling reactivity of biosynthetic enzymes. This project is supported jointly by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences and Chemistry for Life Processes Cluster of Chemistry Division in the Directorate for Mathematical and Physical Sciences.