Mechanism-based inhibitor development for PLP enzymes

BIOL 61

David L. Nelson, chemdave@unlserve.unl.edu, Bradley D. Charette, Ronald L. Cerny, and David B. Berkowitz, dbb@unlserve.unl.edu. Department of Chemistry, University of Nebraska, 824 Hamilton Hall, Lincoln, NE 68588-0304
Our research group has been active in the design, synthesis and evaluation of unnatural amino acids as mechanism-based inhibitors for pyridoxal phosphate (PLP)-enzymes. Initial efforts in this area specifically targeted amino acid decarboxylase enzymes. For example, we chose to replace the alpha-proton with a vinyl or halovinyl group, resulting in a quaternary, beta,gamma-unsaturated amino acid design. This was particularly successful in the active site of lysine decarboxylase (JACS, 2007, 129, 258-9). Herein, our general stategies for decarboxylase enzymes will be outlined, as will our more recent efforts to examine PLP enzymes that labilize the C-alpha-H bond. Inhibitor design/synthesis strategies, enzyme purification and inhibition studies will be presented.