S-Aryl-L-cysteine S,S-dioxides: design, synthesis, and evaluation of a new class of inhibitors of kynureninase

• Published in: Journal of the American Chemical Society Vol. 115; no. 4; pp. 1264 - 1270
• Main Authors: Dua, Rajesh K, Taylor, Ethan W, Phillips, Robert S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.02.1993; Amer Chemical Soc
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Chemistry; Chemistry, Multidisciplinary; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Physical Sciences; Science & Technology; QUINOLINIC ACID; BINDING; FIELD; LYASE; ESCHERICHIA-COLI; DISEASE; Enzymatic activity; Microbial origin; Enzyme; Enzyme inhibitor; Kynureninase; Chemical synthesis; Modeling; Structural analysis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00057a007

The design, preparation, and evaluation of S-aryl-L-cysteine S,S-dioxides, a new class of potent competitive inhibitors of kynureninase from Pseudomonas fluorescens, are described. The most potent of these compounds, S-(2-aminophenyl)-L-cysteine S,S-dioxide, has a K(i) value of 70 nM. These analogues form prominent visible absorption peaks at 500 nm, assigned to quinonoid intermediates, when bound to kynureninase. Titration of kynureninase with S-(2-aminophenyl)-L-cysteine S,S-dioxide demonstrates that 1 mol of the inhibitor is bound to the pyridoxal 5'-phosphate in each subunit. Comparative molecular field analysis of the effects of structural variation on inhibitory potency allows us to predict that the (S)-gem-diolate anion of L-kynurenine, a proposed reaction intermediate, binds with a K(D) of 19 nM. These results provide strong additional support for the intermediacy of a gem-diol or gem-diolate anion in the reaction mechanism of kynureninase.