Scott
Lefurgy
Chemical
Biology & Science Education
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 photo: Alan Orling
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Scott Travis Lefurgy,
Ph.D
Postdoctoral Research Associate Thomas S. Leyh Laboratory Ullmann Building Room 111 Albert Einstein College of Medicine 1300 Morris Park Avenue Bronx, NY 10463 USA 718-430-2858 slefurgy@aecom.yu.edu |
| Current Research My research in the Leyh Lab focuses on the development of a new antibiotic with exquisite selectivity for Streptococcus pneumoniae. Recently, our laboratory identified the mevalonate pathway of isoprenoid biosynthesis in S. pneumoniae as a novel antibiotic target. This little-studied pathway involves three enzymes in the GHMP kinase family: mevalonate kinase, phosphomevalonate kinase and diphosphomevalonate decarboxylase, which convert mevalonate to isopentenyl diphosphate--the precursor to a wide family of lipids including cholesterol, farnesyl- and geranyl-diphosphate. An intermediate in this pathway, diphosphomevalonate (DPM), strongly and non-competitively inhibits the activity of S. pneumoniae mevalonate kinase, but binds weakly to to the human ortholog at physiologically relevant concentrations. Additionally, derivatives of DPM have been shown to strongly and covalently inhibit the decarboxylase, making DPM an ideal lead compound for a two-fisted antibiotic strategy. My research involves determination of the mechanism of inhibition by DPM and its derivatives for both enzyme targets. The first part of this work will involve looking at mevalonate kinases in related pathogenic gram-positive bacteria to determine the scope of inhibition by DPM. In collaboration with medicinal chemists, we are developing compounds that will help us understand the structure and mechanism of mevalonate kinase through a combination of NMR spectroscopy and initial rate kinetics. Graduate Research My research in the Cornish lab focuses on the mechanism of beta-lactamases, the enzymes responsible for bacterial resistance to penicillin and similar antibiotics. I use high-throughput screening and selection in combination with modern molecular biology techniques in order to study the activity of the P99 cephalosporinase from Enterobacter cloacae and its mutants. The active site residues of this enzyme are highly conserved across all species, particularly the putative general base residues Lys67 and Tyr150. Previous mutagenesis studies have shown that mutation of either residue results in a substrate-dependent loss of activity. In other words, the removal of one potential general base has very minimal effect on activity toward certain substrates, and a large effect toward others. This result is puzzling, and suggests that either one or the other residue may act as the general base, or perhaps even both simultaneously, depending on the positioning of the substrate. Through combinatorial saturation mutagenesis of the active site, I hope to demonstrate that the nature of the general base in P99 cephalosporinase is fluid and can be made to shift from one residue to another through mutation. Undergraduate Research As an undergraduate at the Universitiy of Michigan, Ann Arbor, I studied the role of the 33 kDa extrinsic manganese-stabilizing protein in spinach Photosystem II, in the laboratory of Prof. Charles Yocum. In addition, I worked with Prof. Brian Coppola to develop, implement, and assess a molecular modeling component in the honors organic chemistry sequence, for which we were awarded the Undergraduate Computational Engineering and Science Award from the Department of Energy. I also worked on a project with the Highly Interactive Computing for Education consortium co-led by Prof. Elliot Soloway from the School of Information, Prof. Joseph Krajcik from the School of Education, and Prof. Coppola to design eChem, a software package for high school students.  Figure
1. The active site of P99 cephalorsporinase
(stereo image)
"Chemical Complementation" in Enzyme Assays (Wiley-VCH) Finding
Cinderella After the Ball (Chemistry
& Biology)
Cornish Lab Members  photo: Alan Orling |
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