Grant: $258,888 - National Institutes of Health - Sep. 25, 2009
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Award Description: Many natural products contain cyclopropane, oxirane, or aziridine groups as key structural elements. These three-membered ring moieties are generally stable despite their considerable ring strain. However, the inherent reactivities of these small rings can be released by enzymatic activation. Such activation often leads to reactive intermediates that inhibit the corresponding enzyme, making these three-membered ring containing compounds potential drugs. Although these small ring structures have a long history as therapeutic agents and mechanistic probes, little is known about how they are constructed in nature. To explore the biosynthesis of these strained ring compounds and to facilitate drug design efforts, we have chosen to study several intriguing enzymes involved in oxirane and aziridine formation. These include (S)-2- hydroxypropylphosphonate epoxidase (HppE) and 2-hydroxyethylphosphonate methyltransferase (HepM) in the fosfomycin biosynthetic pathway, and the enzymes catalyzing aziridine ring formation in the azicemicin A biosynthetic pathway. These enzymes were selected for their significant biological roles, their novel catalytic mechanisms, and their potential as catalysts for the combinatorial biosynthesis of new therapeutics. The proposed experiments will address the following specific aims: (1) to investigate the catalytic mechanism of HppE, including the oxygen activation mechanism and the chemical nature of the reaction intermediates; (2) to characterize the catalytic properties of HepM, especially the functions of methylcobalamin and radical- SAM in catalysis, and the mechanism of the methylation reaction; (3) to establish the biosynthetic pathway of aziridine ring formation in azicemicin A, and to characterize the key enzymes involved in the transformation. These studies will not only lead to a better understanding of the catalytic mechanism of the targeted enzymes, but will also provide important insight for designing methods to control and mimic the catalytic functions of related enzymes, many of which are medically relevant. Our results are expected to contribute to the broad field of natural product biosynthesis and mechanistic enzymology, and may also assist future clinical applications for the development of new metabolites using pathway engineering and/or combinatorial biosynthetic methods.
Project Description: Project was funded on September 25. Work has not yet commenced.
Jobs Summary: Work has not yet commenced. (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 25, 2009. Help expand these official descriptions using the wiki below.