Journal article
Probing the Active Sites of Butyrylcholinesterase and Cholesterol Esterase with Isomalathion: Conserved Stereoselective Inactivation of Serine Hydrolases Structurally Related to Acetylcholinesterase
Chemical research in toxicology, Vol.14(7), pp.807-813
07/16/2001
DOI: 10.1021/tx015501s
PMID: 11453726
Abstract
Previous work has shown that acetylcholinesterase (AChE), a member of the α/β-hydrolase superfamily, is stereoselectively inhibited by the four stereoisomers of isomalathion. Recent kinetic and mass spectral data demonstrated that a difference in mechanism of inactivation exists for AChE treated with (1R)- versus (1S,3S)-stereoisomers. This study sought to determine whether other α/β-hydrolases are stereoselectively inhibited by isomalathion and if the difference in mechanism of AChE inactivation between (1R)- and (1S,3S)-isomers is conserved for other α/β-hydrolases. Bimolecular rate constants of inhibition (k i) were measured for human and equine butyrylcholinesterase (HBChE and EBChE, respectively) and bovine cholesterol esterase (BCholE) with all four isomers. Isomalathion isomers inhibited these enzymes with the following order of potency: (1R,3R) > (1R,3S) > (1S,3R) ≥ (1S,3S). Ratios of k i values for the most potent to the least potent isomer were 10.5 (HBChE), 11.9 (EBChE), and 68.6 (BCholE). Rate constants of reactivation (k 3) were measured for enzyme inhibited by isomalathion isomers. HBChE, EBChE, and BCholE inactivated by the (1R)-isomers readily reactivated. However, enzymes modified by (1S)-isomalathions were refractory toward reactivation, and k 3 values were not significantly different from zero for HBChE and BCholE treated with the (1S,3S)-isomer. Computer-based docking experiments were performed for BCholE with (1R,3R)- and (1S,3S)-enantiomers. Calculated structures predicted a difference in primary leaving group: diethyl thiosuccinate for (1R,3R)-isomalathion and thiomethyl for the (1S,3S)-isomer. The data demonstrate that the α/β-hydrolases used in this study are stereoselectively inhibited by isomalathion. Furthermore, the results suggest that the mechanistic shift demonstrated to occur for inhibition of AChE by (1R)- versus (1S,3S)-isomers is conserved for butyrylcholinesterase and cholesterol esterase.
Details
- Title: Subtitle
- Probing the Active Sites of Butyrylcholinesterase and Cholesterol Esterase with Isomalathion: Conserved Stereoselective Inactivation of Serine Hydrolases Structurally Related to Acetylcholinesterase
- Creators
- Jonathan A DoornTodd T TalleyCharles M ThompsonRudy J Richardson
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.14(7), pp.807-813
- Publisher
- American Chemical Society
- DOI
- 10.1021/tx015501s
- PMID
- 11453726
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Language
- English
- Date published
- 07/16/2001
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984070209502771
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