Research

My work focuses on a subclass of flavin-dependent monooxygenases that are necessary for the production of hydroxymate siderophores in many pathogenic microbes. As a consequence of the necessity for iron in many organisms, microbial systems have developed highly intricate methods for acquisition of this essential but highly insoluble metal. At the focal point of iron acquisition in many pathogenic microbes are hydroxymate siderophores. Microbes produce these small molecular weight metabolites that have a high affinity for ferric-iron to fulfill their nutritional iron demand during iron-deficient conditions. A larger goal of the mechanistic work acquired to date with the ornithine monooxygenase from Aspergillus fumigatus has been to support the rational development of inhibitors. A detailed spectroscopic study supports a kinetic mechanism similar to that of the hepatic flavin monooxygenases and bacterial Baeyer-Villiger monooxygenases, with which they share moderate homology and from which they are distinguished by their acute substrate specificity. Current objectives are to obtain structural information on the NADP- and ornithine-pocket by use of various techniques, including circular dichroism, fluorescence and NMR spectroscopy. One goal is to describe the orientation of NADP in the active site and determine if this falls into any other known pharmacofamilies. In addition, we have demonstrated kinetically there are two binding sites for the hydroxylatable substrate, ornithine. We would like to better understand this substrate interaction in order to define substrate discrimination. Understanding the active site pocket, as it is poised for oxygenation will support a rational development of inhibitors.

Awards and Honors

Chemistry Biochemistry Biology Interface Graduate Fellowship, August 2008 – present

Publications

Frederick, R. F.; Mayfield, J. A.; DuBois, J. L. Iron trafficking as an antimicrobial target, Biometals 2009, 22, 583.