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Reversible Inhibition of Acetylcholinesterase and Butyrylcholinesterase by 4,4'-bipyridine and by a Coumarin Derivative

Reversible Inhibition of Acetylcholinesterase and Butyrylcholinesterase by 4,4'-bipyridine and by a Coumarin Derivative

V Simeon-Rudolf, Z Kovarik, Z Radić, E Reiner

Chem Biol Interact. 1999 May 14;119-120:119-28.

PMID: 10421445

Abstract:

Inhibition of recombinant mouse wild type AChE (EC 3.1.1.7) and BChE (EC 3.1.1.8), and AChE peripheral site-directed mutants and human serum BChE variants by 4,4'-bipyridine (4,4'-BP) and the coumarin derivative 3-chloro-7-hydroxy-4-methylcoumarin (CHMC) was studied. The enzyme activity was measured with acetylthiocholine as substrate. Enzyme-inhibitor dissociation constants for the catalytic and peripheral sites were evaluated from the apparent dissociation constants as a function of the substrate concentration. Inhibition by 4,4'-BP of AChE, BChE and the AChE mutant Y72N/Y124Q/W286A, was consistent with inhibitor binding to both catalytic and peripheral sites. The dissociation constants for the peripheral site were about 3.5-times higher than for the catalytic site. The competition between CHMC and substrate displayed two binding sites on the AChE mutants Y72N, Y124Q, W286A and W286R, and on the atypical and fluoride-resistant BChE variants. The dissociation constants for the peripheral site were on average two-times higher than for the catalytic site. CHMC displayed binding only to the catalytic site of Y72N/Y124Q/W286A mutant and only to the peripheral site of w.t. AChE and the human usual BChE. Modelling of the 4,4'-BP and CHMC binding to wild type mouse AChE substantiated the difference between the inhibitors in their mode of binding which was revealed in the kinetic studies.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP6174863	3-Chloro-7-hydroxy-4-methylcoumarin		6174-86-3	Price

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