The synthesis and evaluation of possible “bi-product” based inhibitors of kynureninase, from Pseudomonas fluorescens, and other pyridoxal 5’-phosphate dependent enzymes
Moore, Joseph Alexander
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This research focused on the synthesis of possible new inhibitors for the enzyme kynureninase. The inhibitors were designed based on the substrate, kynurenine, and the products, alanine and anthranilic acid. Derivatives of N3-benzoyl-2,3-diaminopropionic acid were selected; these compounds are "bi-product" analogs in that the alanine and benzoyl group are joined by an amide linkage. These compounds were also tested with two other pyridoxal 5'-phosphate, PLP, dependent enzymes that catalyze reactions of aromatic aminoacids, tryptophan indole-lyase and tyrosine phenol-lyase (TPL), for their inhibiting effect. All the derivatives studied demonstrated similar competitive inhibitor activity towards kynureninase, TPL, and tryptophan indole-lyase. To further understand the mechanism of kynureninase, the steady state kinetics of the kynureninase reactions were investigated. Additional studies to determine the rate limiting step of the mechanism were conducted by investigating the effects of ?-[2H]-L-kynurenine and solvent deuterium.