Differential Inhibition of Six Copper Amine Oxidases by a Family of 4-(Aryloxy)-2-butynamines: Evidence for a New Mode of Inactivation

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• 作者：Kimberly M. O'Connell ; David B. Langley ; Eric M. Shepard ; Anthony P. Duff ; Heung-Bae Jeon ; Gang Sun ; Hans C. Freeman ; J. Mitchell Guss ; Lawrence M. Sayre ; and David M. Dooley
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：August 31, 2004
• 年：2004
• 卷：43
• 期：34
• 页码：10965 - 10978
• 全文大小：576K
• 年卷期：v.43,no.34(August 31, 2004)
• ISSN：1520-4995

文摘

A series of compounds derived from a previously identified substrate analogue of copper amineoxidases (CuAOs) (Shepard et al. (2002) Eur. J. Biochem. 269, 3645-3658) has been screened againstsix different CuAOs with a view to designing potent and selective inhibitors. The substrate analoguesinvestigated were 4-(1-naphthyloxy)-2-butyn-1-amine, 4-(2-methylphenoxy)-2-butyn-1-amine, 4-(3-methylphenoxy)-2-butyn-1-amine, 4-(4-methylphenoxy)-2-butyn-1-amine, and 4-phenoxy-2-butyn-1-amine.These compounds were screened against equine plasma amine oxidase (EPAO), Pisum sativum amineoxidase (PSAO), Pichia pastoris lysyl oxidase (PPLO), bovine plasma amine oxidase (BPAO), humankidney diamine oxidase (KDAO), and Arthrobacter globiformis amine oxidase (AGAO) to examine theeffect of different substituent groups on potency. Despite the similar structures of the 4-aryloxy analoguesevaluated, striking differences in potency were observed. In addition, crystal structures of AGAO derivitizedwith 4-(2-naphthyloxy)-2-butyn-1-amine and 4-(4-methylphenoxy)-2-butyn-1-amine were obtained at aresolution of 1.7 Å. The structures reveal a novel and unprecedented reaction mechanism involving covalentattachment of the ,-unsaturated aldehyde turnover product to the amino group of the reduced 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. Collectively, the structural and inhibition results supportthe feasibility of designing selective mechanism-based inhibitors of copper amine oxidases.