title: A comparative study on the inhibition of human and bacterial kynureninase by novel bicyclic kynurenine analogues.
abstract: A series of novel bicyclic analogues of kynurenine were synthesised as inhibitors of kynureninase. The tryptophan-induced bacterial enzyme from Pseudomonas. fluorescens was compared to the constitutive recombinant human enzyme expressed in a baculovirus/insect cell system, with regard to their inhibition by these compounds. All the compounds studied were found to be simple competitive, reversible inhibitors of kynureninase. It was found that altering the size of the second ring of the inhibitor affected the observed Ki values for both enzymes. The addition of an oxygen atom into the second ring had little effect on binding to the bacterial enzyme but gave a more potent inhibitor of human kynureninase. Of the compounds tested, a naphthyl analogue of desaminokynurenine was found to be the most potent inhibitor for both enzymes with Ki values of 5 and 22 microM for bacterial and human enzyme respectively. This report also describes an alternative system for the expression of recombinant human kynureninase which is more convenient for expression in mammalian cells and produces a relatively greater quantity of enzyme.
authors.affiliation: School of Chemistry University of St. Andrews, Fife, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Fitzgerald
authors.forename: K M
authors.initials: KM
authors.lastname: Muirhead
authors.forename: N P
authors.initials: NP
authors.lastname: Botting
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007313:Insecta; D007700:Kinetics; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D011551:Pseudomonas fluorescens / Q000187:drug effects / Q000201:enzymology; D011994:Recombinant Proteins
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D007737:Kynurenine; D006867:Hydrolases; C021480:kynureninase