1SIH

AGAO in covalent complex with the inhibitor MOBA ("4-(4-methylphenoxy)-2-butyn-1-amine")

Summary for 1SIH

• Entry DOI: 10.2210/pdb1sih/pdb
• Related: 1AV4 1SII
• Descriptor: Phenylethylamine oxidase, SULFATE ION, COPPER (II) ION, ... (6 entities in total)
• Functional Keywords: cao, cuao, copper-containing, amine oxidase, tpq, quinone, trihydroxyphenylalanine quinone, moba, 4-(4-methylphenoxyoxy)-2-butyn-1-amine, 4-(aryloxy)-2-butynamine, suicide inhibition, oxidoreductase
• Biological source: Arthrobacter globiformis
• Total number of polymer chains: 1
• Total formula weight: 72305.79

Authors

Guss, J.M.,Langley, D.B.,Duff, A.P. (deposition date: 2004-02-29, release date: 2004-09-07, Last modification date: 2024-10-30)

Primary citation

O'Connell, K.M.,Langley, D.B.,Shepard, E.M.,Duff, A.P.,Jeon, H.B.,Sun, G.,Freeman, H.C.,Guss, J.M.,Sayre, L.M.,Dooley, D.M.
Differential Inhibition of Six Copper Amine Oxidases by a Family of 4-(Aryloxy)-2-butynamines: Evidence for a New Mode of Inactivation.
Biochemistry, 43:10965-10978, 2004

PubMed Abstract: 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.

PubMed: 15323556
DOI: 10.1021/bi0492004

Experimental method

X-RAY DIFFRACTION (1.73 Å)