Pratt, Rex - Wesleyan University - Department of Chemistry

个人简介

BS University of Melbourne MAA Wesleyan University PHD University of Melbourne

研究领域

Biochemistry: Enzyme kinetics and mechanisms; bio-organic chemistry; beta-lactamases and beta-lactam antibiotics; enzyme inhibitor design. Biological chemistry involves chemical reactions which are relevant, directly or indirectly, to biological systems. There are, of course, many different reactions that can fall into this category and an almost equal number of ways in which they can be studied. My approach, which derives from a background of physical organic aqueous solution chemistry, is directed towards an understanding of the mechanisms of these reactions. Since chemical reactions in living systems are usually enzyme catalyzed, some understanding of enzyme mechanisms in fundamental to biological chemistry. One can divide this problem, on paper at least, into two parts. First what is the chemistry involved, i.e., what functional groups on an enzyme interact, covalently or non-covalently, with the substrate, and how do they catalyze the reaction? Second, what is the role of the rest of the protein, i.e., how does the static and dynamic structure of the whole protein molecule contribute to its function? With these general questions in mind we have concentrated on a particular group of bacterial enzymes, those specifically interacting with ß-lactam antibiotics, the penicillins and cephalosporins. One important class of these enzymes, the ß-lactamases, catalyzes the hydrolysis and thus destruction of ß-lactam antibiotics and is the major source of bacterial penicillin resistance, while another, the D-alanine transpeptidases, is involved in bacterial cell wall synthesis and is the site of the antibiotic action of these drugs. These enzymes are thus of practical or clinical importance as well as of fundamental interest. Until recently very little was known about the mechanism of action of these groups of enzymes and the relationships between their active sites. The substrate specificity of the transpeptidases was also not well established. Our approach to mechanistic problems of this type is through the design and synthesis of new enzyme substrates and inhibitors, and study of their modes of interaction with the relevant enzymes by means of the methods of enzyme kinetics and physical organic chemistry. The rich chemistry of ß-lactams permits the design of very subtle active site probes. Crystal structures of enzyme/inhibitor complexes, aided by computational modeling, can lead to further inhibitor design.

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J.H. Bell, K. Curley and R.F. Pratt, “Inhibition of Serine Amidohydrolases by Complexes of Vanadate with Hydroxamic Acids”, Biochem. Biophys. Res. Commun. 274, 732 (2000). K. Kaur and R.F. Pratt, “Mechanism of Reaction of Acyl Phosph(on)ates with the ß-Lactamase of Enterobacter cloacae P99″, Biochemistry 40, 4610 (2001). S.A. Adediran, D. Cabaret, B. Drusilla, R.F. Pratt, and M. Wakselman, “The Synthesis and Evaluation of Benzofuranones as ß-Lactamase Substrates”, Bioorg. Med. Chem. 9, 1175 (2001). S. Kumar, S.L. Pearson, and R.F. Pratt, “Design, Synthesis, and Evaluation of alpha-Ketoheterocycles as Class C ß-Lactamase Inhibitors” Biooorg. Med. Chem.9, 2035 (2001). M.J. Morrison, N. Li, and R.F.Pratt, “Inverse Acyl Phosph(on)ates: Substrates or Inhibitors of ß-Lactam-Recognizing Enzymes” Bioorg. Chem. 29, 271 (2001). K. Kaur, M.J.K. Lan, and R.F. Pratt, “Mechanism of Inhibition of the Class C ß-Lactamase of Enterobacter cloacae by Cyclic Acyl Phosph(on)ates: Rescue by Return” J. Amer. Chem. Soc.123, 10436 (2001). R.F. Pratt, “Functional Evolution of the ß-Lactamase Active Site”, J. Chem. Soc. Perkin Trans. II, 851 (2002). J.H. Bell and R.F. Pratt, “Mechanism of Inhibition of the ß-Lactamase of Enterobacter cloacae P99 by 1:1 Complexes of Vanadate with Hydroxamic Acids”, Biochemistry41, 4329 (2002). J.H. Bell and R.F. Pratt, “Formation and Structure of 1:1 Complexes Between Aryl Hydroxamic Acids and Vanadate at neutral pH”, Inorg. Chem. 41, 2747 (2002). M.A. McDonough, J.W. Anderson, N.R. Silvaggi, R.F. Pratt, J.R. Knox and J.A. Kelly, “Structures of Two Kinetic Intermediates Reveal Species Specificity of Penicillin-binding Proteins”, J. Mol. Biol.322, 111 (2002). N.R. Silvaggi, J.W. Anderson, S.R. Brinsmade, R.F. Pratt and J.A. Kelly, “The Crystal Structure of Phosphonate-Inhibited D-Ala-D-Ala peptidase Reveals an Analogue of a Tetrahedral Transition State” Biochemistry42, 1199 (2003). K. Kaur, S.A. Adediran, M.J.K. Lan and R.F. Pratt, “Inhibition of ß-Lactamases by Monocyclic Acyl Phosph(on)ates” Biochemistry42, 1429 (2003). D. Cabaret, S.A. Adediran, R.F. Pratt and M. Wakselman, “New Substrates for ß-Lactam-Recognizing Enzymes: Aryl Malonamates” Biochemistry 42, 6719 (2003). J.W. Anderson, S.A. Adediran, P. Charlier, M. Nguyen-Disteche, J-M. Frere, R.A. Nicholas, and R.F.Pratt, “On the Substrate Specificity of Bacterial DD-Peptidases: Evidence from two Series of Peptidoglycan-mimetic Peptides” Biochem.J. 373, 949 (2003). M. Nukaga, S. Kumar, K. Nukaga, R. F. Pratt and J. R. Knox, Hydrolysis of Third-generation Cephalosporins by Class C ß-Lactamases: Structures of a Transition State Analog of Cefotaxime in Wild-type and Extended Spectrum Enzymes J. Biol. Chem. 279, 9344 (2004). S. Kumar, S. A. Adediran, M. Nukaga and R. F. Pratt, Kinetics of Turnover of Cefotaxime by the Enterobacter cloacae P99 and GCl ß-Lactamases: Two Free Enzyme Forms of the P99 ß-Lactamase Detected by a Combination of Pre- and Post-Steady State Kinetics Biochemistry 43, 2664 (2004). Y.M. Ahn and R. F. Pratt, Kinetic and Structural Consequences of the Leaving Group in Substrates of a Class C ß-Lactamase Bioorg. Med. Chem. 12, 1537 (2004). N.R. Silvaggi, K. Kaur, S.A. Adediran, R.F. Pratt, and J.A. Kelly, “Toward Better Antibiotics: Crystallographic Studies of a Novel Class of DD-Peptidase/ß-Lactamase Inhibitors” Biochemistry 43, 7046 (2004). H.J. Josephine, I. Kumar, and R.F. Pratt, “The Perfect Penicillin? Inhibition of a Bacterial DD-Peptidase by Peptidoglycan-Mimetic ß-Lactams” J. Amer. Chem. Soc. 126, 8122 (2004). R. Nagarajan and R.F. Pratt, “Thermodynamic Evaluation of a Covalently Bonded Transition State Analogue Inhibitor: Inhibition of ß-Lactamases by Phosphonates” Biochemistry 43, 9664 (2004).