168154-85-6Relevant articles and documents
Substituent effects on the reaction of β-benzoylalanines with Pseudomonas fluorescens kynureninase
Kumar, Sunil,Gawandi, Vijay B.,Capito, Nicholas,Phillips, Robert S.
experimental part, p. 7913 - 7919 (2011/11/06)
Kynureninase is a pyridoxal 5′-phosphate-dependent enzyme that catalyzes the hydrolytic cleavage of l-kynurenine to give l-alanine and anthranilic acid. β-Benzoyl-l-alanine, the analogue of l-kynurenine lacking the aromatic amino group, was shown to a good substrate for kynureninase from Pseudomonas fluorescens, and the rate-determining step changes from release of the second product, l-Ala, to formation of the first product, benzoate [Gawandi, V. B., et al. (2004) Biochemistry 43, 3230-3237]. In this work, a series of aryl-substituted β-benzoyl-dl-alanines was synthesized and evaluated for substrate activity with kynureninase from P. fluorescens. Hammett analysis of kcat and kcat/Km for 4-substituted β-benzoyl-dl-alanines with electron-withdrawing and electron-donating substituents is nonlinear, with a concave downward curvature. This suggests that there is a change in rate-determining step for benzoate formation with different substituents, from gem-diol formation for electron-donating substituents to Cβ-Cγ bond cleavage for electron-withdrawing substituents. Rapid-scanning stopped-flow kinetic experiments demonstrated that substituents have relatively minor effects on formation of the quinonoid and 348 nm intermediates but have a much greater effect on the formation of the aldol product from reaction of benzaldehyde with the 348 nm intermediate. Since there is a kinetic isotope effect on its formation from β,β-dideuterio-β-(4-trifluoromethylbenzoyl)-dl- alanine, the 348 nm intermediate is proposed to be a vinylogous amide derived from abortive β-deprotonation of the ketimine intermediate. These results provide additional evidence for a gem-diol intermediate in the catalytic mechanism of kynureninase.
2-AMINO-4-PHENYL-4-OXO-BUTYRIC ACID DERIVATIVES
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, (2008/06/13)
Use in the prevention and/or in the treatment of neurodegenerative diseases of 2-amino-4-phenyl-4-oxo-butyric acid derivatives which act as kynureninase enzyme inhibitors and/or kynurenine-3-hydroxylase enzyme inhibitors. Several of these derivatives are new and, as such, constitute a further object of this invention, together with the process for their preparation and the pharmaceutical compositions containing them.
