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Reaction dynamics and transition-state structures for acetylcholinesterase-catalyzed hydrolysis of aryl esters and anilides

Thesis/Dissertation ·
OSTI ID:6950174

The acylation and deacylation stages of acetylcholinesterase-catalyzed hydrolysis of various aryl ester and anilide substrates were investigated. For the natural substrate of acetylcholinesterase (AChE), acetylcholine, diffusion or enzyme conformational processes limit the acylation rate. Several anilides and aryl esters have been synthesized and found to be substrates of AChE. The acylation and deacylation reactivities of o-nitroformanilide, p-methoxyphenyl formate and o-nitrophenyl acetate were characterized by measuring substrate secondary and solvent isotope effects and by determining pL(L = H,D)-rate profiles and Eyring plots. Substrate secondary deuterium kinetic isotope effects are consistent with decreasing nucleophilic interaction at the carbonyl carbon of the scissle bond of the substrate in the rate-determining transition state with increasing V/K. These results lend quantitative support to a model for acylation rate determination involving a virtual transition state that contains contributions from the transition states of sequential physical and chemical steps.

Research Organization:
Iowa Univ., Iowa City (USA)
OSTI ID:
6950174
Country of Publication:
United States
Language:
English

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
400202* -- Isotope Effects
Isotope Exchange
& Isotope Separation
ACETYLCHOLINE
AMINES
AMMONIUM COMPOUNDS
ARYL RADICALS
AUTONOMIC NERVOUS SYSTEM AGENTS
CATALYSIS
CATALYTIC EFFECTS
CHEMICAL REACTIONS
DECOMPOSITION
DRUGS
ENZYMES
ESTERASES
ESTERS
HEAVY WATER
HYDROGEN COMPOUNDS
HYDROLASES
HYDROLYSIS
ISOTOPE EFFECTS
LYSIS
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXYGEN COMPOUNDS
PARASYMPATHOMIMETICS
QUATERNARY COMPOUNDS
RADICALS
SOLVOLYSIS
WATER