Current Research Projects-General Description

          Our general research interests are in the area of biological chemistry. Currently, we are engaged in three projects. One of these is aimed at the discovery of the mechanism(s) of directed protein evolution in microbes. By learning how genes are recruited and retooled for adaptation to sudden influxes of toxins or unnatural organics, strategies for inhibiting the acquisition of drug resistance should follow. In addition, we hope to uncover general strategies which can be used to engineer new chemical pathways in microorganisms for application in relay synthesis and bioremediation. At the moment , studies are focused on the elucidation of the chemistry and genetics of the 4-chlorobenzoate degrading pathway recruited by soil bacterial residents of polychlorinated biphenyl (PCBs) spill sites.

         A second area of investigation is concerned with the biochemistry of natural and synthetic phosphonates. Phosphonates belong to a growing family of biologically active organophosphorus compounds containing P-C bonds. Phosphonates are chemically stable phosphate ester analogs and, as such, find widespread use as herbicides, pesticides and pharmaceutical agents. Natural phosphonates are diverse both in structure and occurrence. In certain strains of bacteria, they are produced as secondary metabolites having antibiotic activity. Their physiological functions in higher organisms are largely unknown but evidence which links them to cell signaling processes has been reported. Studies are presently being conducted to define the biosynthetic and biodegradative pathways of phosphonates and the mechanisms of the enzymes catalyzing P-C formation and cleavage.
        A third area of study is concerned with the mechanism and dynamics of domain movement within proteins. For proteins in which function is coupled to physical translocation the use of structural domains to mediate movement may be a common solution. For instance, catalysis at separate active sites in some multienzyme complexes is linked by a carrier arm, transported by movement of the domain to which it is appended. In the model system under study in our laboratory, pyruvate phosphate dikinase (PPDK), catalysis of ATP and pyruvate partial reactions takes place at two different active sites linked by a carrier histidine. The active sites are located on the N-terminal and C-terminal domains of this 3-domain protein. The central domain, containing the carrier histidine, plays a go-between role between the substrate binding domains. At the present we are carrying out structural and dynamic studies of the domain movement occurring during catalytic turnover. The goal of these studies is to learn how protein-protein and protein-ligand interactions facilitate productive domain-domain binding.

Current Research Funding:

NIH Grant GM 28688 Mechanisms of Enzyme Reactions 2/01/98- 1/31/02

NIH Grant 36260 Investigation of Pyruvate Phoshate Dikinase 4/01/95-3/31/99

       Back to DDM's Group homepage

For more information contact