1sii
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AGAO in covalent complex with the inhibitor NOBA ("4-(2-naphthyloxy)-2-butyn-1-amine")
OverviewOverview
A series of compounds derived from a previously identified substrate, analogue of copper amine oxidases (CuAOs) (Shepard et al. (2002) Eur. J., Biochem. 269, 3645-3658) has been screened against six different CuAOs, with a view to designing potent and selective inhibitors. The substrate, analogues investigated 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 amine oxidase (PSAO), Pichia pastoris lysyl oxidase (PPLO), bovine, plasma amine oxidase (BPAO), human kidney diamine oxidase (KDAO), and, Arthrobacter globiformis amine oxidase (AGAO) to examine the effect of, different substituent groups on potency. Despite the similar structures of, the 4-aryloxy analogues evaluated, striking differences in potency were, observed. In addition, crystal structures of AGAO derivitized with, 4-(2-naphthyloxy)-2-butyn-1-amine and 4-(4-methylphenoxy)-2-butyn-1-amine, were obtained at a resolution of 1.7 A. The structures reveal a novel and, unprecedented reaction mechanism involving covalent attachment of the, alpha,beta-unsaturated aldehyde turnover product to the amino group of the, reduced 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor., Collectively, the structural and inhibition results support the, feasibility of designing selective mechanism-based inhibitors of copper, amine oxidases.
About this StructureAbout this Structure
1SII is a Single protein structure of sequence from Arthrobacter globiformis with CU, NA, SO4 and GOL as ligands. Active as Amine oxidase (copper-containing), with EC number 1.4.3.6 Full crystallographic information is available from OCA.
ReferenceReference
Differential inhibition of six copper amine oxidases by a family of 4-(aryloxy)-2-butynamines: evidence for a new mode of inactivation., O'Connell KM, Langley DB, Shepard EM, Duff AP, Jeon HB, Sun G, Freeman HC, Guss JM, Sayre LM, Dooley DM, Biochemistry. 2004 Aug 31;43(34):10965-78. PMID:15323556
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