Differential inhibition of six copper amine oxidases by a family of 4-(aryloxy)-2-butynamines: evidence for a new mode of inactivation.
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.
O'Connell
Kimberly M
KM
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, USA.
Langley
David B
DB
Shepard
Eric M
EM
Duff
Anthony P
AP
Jeon
Heung-Bae
HB
Sun
Gang
G
Freeman
Hans C
HC
Guss
J Mitchell
JM
Sayre
Lawrence M
LM
Dooley
David M
DM
D000499:Allylamine / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry*; D000818:Animals; D001173:Arthrobacter / Q000201:enzymology; D002417:Cattle; D003067:Coenzymes / Q000737:chemistry; D018360:Crystallography, X-Ray; D003959:Diamines / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006736:Horses; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D018532:Pisum sativum / Q000201:enzymology; D010843:Pichia / Q000201:enzymology; D011437:Propylamines / Q000494:pharmacology; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D011809:Quinones / Q000737:chemistry
C086758:2,4,5-trihydroxyphenylalanine quinone; C464879:4-(2-naphthyloxy)-2-butyn-1-amine; D003067:Coenzymes; D003959:Diamines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011437:Propylamines; D011809:Quinones; C116897:iminoquinone; C009054:propargylamine; D000499:Allylamine; C063335:1,4-diamino-2-butyne; D004295:Dihydroxyphenylalanine; D010293:Pargyline; D008249:Protein-Lysine 6-Oxidase; D006631:Amine Oxidase (Copper-Containing)