Molecular Biophysics


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Linda C. Kurz, Ph.D

Research Assistant Professor
Department of Biochemistry and Molecular Biophysics

The molecular origins of the extraordinary catalytic power of enzymes continue as one of the major questions in biochemistry. image We are concentrating on citrate synthases. These enzymes are prominent in the energy-yielding pathways of a large variety of organisms from psychrophiles to hyperthermophiles. Citrate synthases are prototypes for several important catalytic strategies: carbonyl polarization to increase reactivity of the electrophilic substrate, facilitation of formation of a nucleophilic substrate carbanion, the use of unusual ionization states of histidine residues as acid catalysts, and changes in macromolecular conformation. Previous work in our laboratory has concentrated on demonstrating the existence and importance of carbonyl polarization and carbanion formation. Our present emphasis is on largely unanswered questions of their structural base. We are using the techniques of site-directed mutagenesis to selectively alter residues in the active site and elsewhere guided by the predictions of structural and theoretical studies. In addition to transient and steady-state kinetic methods, we use techniques such as FTIR and NMR spectroscopy, which are sensitive to local bond distortions, electronic environment, and other factors likely to reflect operation of the catalytic machinery. In a new project, we are investigating the catalytic role of protein dynamics and flexibility by detailed mechanistic comparisons in a series of structurally homologous citrate synthases originating in organisms optimized to function at widely different temperatures. We are correlating the relative stabilities of the intermediates and transition states with temperature revealing which elementary steps in the mechanism are modulated by protein flexibility and dynamics.