As part of a program on mechanism-based inactivators (MBIs) for pyridoxal phosphate (PLP)-dependent enzymes, we have been particularly focused on the development of fundamentally new classes of quaternary, α-fluorovinyl amino acids (AAs). Two classes of these AAs have been synthesized in our laboratory for the first time and will be discussed herein; namely α-(2’Z-fluoro)vinyl- and α-(1’-fluoro)vinyl-AAs. These unnatural AAs approach the target enzyme bearing an unreactive isolated fluorovinyl group, initially. However, they are designed to divert the normal enzyme mechanism into an inhibitory pathway, leading to the formation of a reactive intermediate, with the species formed depending upon the position of the fluorine in the trigger and the particular mechanistic pathway(s) followed) in the target active site. In each case, new chemistry has been developed to access these unnatural AAs and will be described. Lysine decarboxylase (LDC) from <i>Hafnia alvei</i> serves as a model PLP enzyme to test inhibitor design and efficicacy for both triggers. Fluorine serves both a mechanistic and analytical chemistry role in these inhibitors. MBI performance and mechanism are studied by a combination of time-dependent enzyme inactivation kinetics (Kitz-Wilson analysis), <sup>19</sup>F NMR, equilibrium dialysis, and external nucleophile protection experiments.

Design, synthesis and evaluation of fluorovinyl triggers for pyridoxal phosphate dependent enzyme inactivation

256th National Meeting (2018)

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