3-Pyrrolines Are Mechanism-Based Inactivators of the Quinone-Dependent Amine Oxidases but Only Substrates of the Flavin-Dependent Amine Oxidases

• Published in: Journal of the American Chemical Society 2002-10, Vol.124 (41), p.12135-12143
• Main Authors: Lee, Younghee, Ling, Ke-Qing, Lu, Xingliang, Silverman, Richard B, Shepard, E. M, Dooley, D. M, Sayre, Lawrence M
• Format: Article
• Language: English
• Subjects: Amine Oxidase (Copper-Containing) - antagonists & inhibitors; Amine Oxidase (Copper-Containing) - metabolism; Analytical biochemistry: general aspects, technics, instrumentation; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Cattle; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Kinetics; Mitochondria, Liver - enzymology; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacology; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Spectrophotometry; Spectrum Analysis, Raman; Substrate Specificity
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0205434

We previously reported that 3-pyrroline and 3-phenyl-3-pyrroline effect a time-dependent inactivation of the copper-containing quinone-dependent amine oxidase from bovine plasma (BPAO) (Lee et al. J. Am. Chem. Soc. 1996, 118, 7241−7242). Quinone cofactor model studies suggested a mechanism involving stoichiometric turnover to a stable pyrrolylated cofactor. Full details of the model studies are now reported along with data on the inhibition of BPAO by a family of 3-aryl-3-pyrrolines (aryl = substituted phenyl, 1-naphthyl, 2-naphthyl), with the 4-methoxy-3-nitrophenyl analogue being the most potent. At the same time, the parent 3-phenyl analogue is a pure substrate for the flavin-dependent mitochondrial monoamine oxidase B from bovine liver. Spectroscopic studies (including resonance Raman) on BPAO inactivated by the 4-methoxy-3-nitrophenyl analogue are consistent with covalent derivatization of the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. The distinction of a class of compounds acting as an inactivator of one amine oxidase family and a pure substrate of another amine oxidase family represents a unique lead to the development of selective inhibitors of the mammalian copper-containing amine oxidases.