Mechanistic and structural approaches for sulfur acquisition in the two-component FMN-dependent monooxygenases

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Many transformations that occur in nature are enhanced by enzymes. Enzymes play an important role in all of life processes, and use unique strategies to optimize the processes they catalyze. Often, enzymes involved in different chemical reactions incorporate similar strategies to ensure the reaction occurs. An important role of enzymes is maintaining appropriate levels of sulfur in the environment to sustain life. An intriguing aspect of enzymes that play a role in sulfur maintenance is that they utilize similar strategies and features, but are involved in different environmental reactions. For example, they all employ a version of riboflavin, vitamin B2. This award from the Chemistry of Life Processes Program in the Chemistry Division to Dr. Holly Ellis of Auburn University provides a unique opportunity to understand how essential enzymes that maintain environmental sulfur levels carry out their reactions. The experiments are designed to evaluate distinct features and strategies of these enzymes, which can be used to study other enzyme families. These investigations are providing graduate and undergraduate students with diverse scientific training and mentoring. Similar experimental techniques are being incorporated into a summer program for incoming freshman underrepresented in the STEM fields at Auburn University.The overall objective of the project is to determine how enzymes belonging to the same family utilize common structural motifs to catalyze different metabolic reactions. The enzymes that catalyze metabolic reactions utilized by bacteria to obtain sulfur have evolved a complex mechanism for sulfur acquisition. These reactions are vital in maintaining adequate cellular sulfur levels. The primary goal of these studies is to determine how the substrate specificity of the two-component FMN monooxygenases is maintained, and evaluate how the structural properties contribute to the specificity and desulfonation mechanism. The structural similarity of two-component FMN-dependent monooxygenases suggests that these enzymes utilize a similar innovative mechanism to catalyze carbon-sulfur bond cleavage. A comprehensive experimental approach is being employed to provide insight into the structure and functional properties of these enzyme systems. The studies proposed are utilizing a tractable system to evaluate a family of enzymes with similar structural and catalytic properties that are involved in a common metabolic goal. The studies described are providing an in-depth investigation on how the structural features of enzymes dictate function, and are providing innovative approaches that can be applied to other enzymes that utilize similar structural features.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.