TAILIEUCHUNG - Báo cáo Y học: Towards the development of selective amine oxidase inhibitors Mechanism-based inhibition of six copper containing amine oxidases

Four substrate analogs, 4-(2-naphthyloxy)-2-butyn-1-amine (1), 1,4-diamino-2-chloro-2-butene (2), 1,6-diamino-2,4hexadiyne (3), and 2-chloro-5-phthalimidopentylamine (4) have been tested as inhibitors against mammalian, plant, bacterial, and fungal copper-containing amine oxidases: bovine plasma amine oxidase (BPAO), equine plasma amine oxidase (EPAO), pea seedling amine oxidase (PSAO), Arthrobacter globiformis amine oxidase (AGAO), Escherichia coli amine oxidase (ECAO), and Pichia pastoris lysyl oxidase (PPLO). Reactions of 1,4-diamino-2-butyne with selected amine oxidases were also examined. Each substrate analog contains a functional group that chemical precedent suggests could produce mechanism-based inactivation. Striking differences in selectivity and rates of inactivation were observed. . | Eur. J. Biochem. 269 3645-3658 2002 FEBS 2002 doi Towards the development of selective amine oxidase inhibitors Mechanism-based inhibition of six copper containing amine oxidases Eric M. Shepard1 Jennifer Smith1 Bradley O. Elmore1 Jason A. Kuchar1 Lawrence M. Sayre2 and David M. Dooley1 1 Department of Chemistry and Biochemistry Montana State University Bozeman MT USA Department of Chemistry Case Western Reserve University Cleveland OH USA Four substrate analogs 4- 2-naphthyloxy -2-butyn-1-amine 1 1 4-diamino-2-chloro-2-butene 2 1 6-diamino-2 4-hexadiyne 3 and 2-chloro-5-phthalimidopentylamine 4 have been tested as inhibitors against mammalian plant bacterial and fungal copper-containing amine oxidases bovine plasma amine oxidase BPAO equine plasma amine oxidase EPAO pea seedling amine oxidase PSAO Arthrobacter globiformis amine oxidase AGAO Escherichia coli amine oxidase ECAO and Pichia pastoris lysyl oxidase PPLO . Reactions of 1 4-diamino-2-butyne with selected amine oxidases were also examined. Each substrate analog contains a functional group that chemical precedent suggests could produce mechanism-based inactivation. Striking differences in selectivity and rates of inactivation were observed. For example between two closely related plasma enzymes BPAO is more sensitive than EPAO to 1 and 3 while the reverse is true for 2 and 4. In general inactivation appears to arise in some cases from TPQ cofactor modification and in other cases from alkylation of protein residues in a manner that blocks access of substrate to the active site. Notably 1 completely inhibits AGAO at stoichiometric concentrations and is not a substrate but is an excellent substrate of PSAO and inhibition is observed only at very high concentrations. Structural models of 1 in Schiff base linkage to the TPQ cofactor in AGAO and PSAO for which crystal structures are available reveal substantial differences in the degree of interaction of bound 1 with sidechain .

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