Journal article
Kinetic Evidence for Different Mechanisms of Acetylcholinesterase Inhibition by (1R)- and (1S)-Stereoisomers of Isomalathion
Toxicology and applied pharmacology, Vol.155(1), pp.43-53
02/15/1999
Handle:
https://hdl.handle.net/2376/107710
PMID: 10036217
Abstract
Inhibition of acetylcholinesterase (AChE) by isomalathion has been assumed to proceed by expulsion of diethyl thiosuccinyl to produceO,S-dimethyl phosphorylated AChE. If this assumption is correct, AChE inhibited by (1R)- or (1S)-isomalathions should reactivate at the same rate as AChE inhibited by configurationally equivalent (S)- or (R)-isoparathion methyl, respectively, which are expected to inhibit AChE by loss of 4-nitrophenoxyl to yieldO,S-dimethyl phosphorylated AChEs. Previous work has shown that rat brain AChE inhibited by (1R)-isomalathions reactivates at the same rate as the enzyme inhibited by (S)-isoparathion methyl. However, although rat brain AChE inhibited by (R)-isoparathion methyl reactivates at a measurable rate, the enzyme inhibited by (1S)-isomalathions is intractable to reactivation. This surprising finding suggests the hypothesis that (1R)- and (1S)-stereoisomers of isomalathion inhibit AChE by different mechanisms, yielding enzymatic species distinguishable by their postinhibitory kinetics. The present study was carried out to test this hypothesis by comparing kinetic constants of reactivation (k+3) and aging (k+4) of hen brain AChE and bovine erythrocyte AChE inhibited by the four stereoisomers of isomalathion and the two stereoisomers of isoparathion methyl. Both AChEs inhibited by either (1R,3R)- or (1R,3S)-isomalathion had comparable correspondingk+3values (spontaneous and oxime-mediated) to those of AChEs inhibited with (S)-isoparathion methyl. However, spontaneous and oxime-mediatedk+3values comparable to those of (R)-isoparathion methyl could not be obtained for AChEs inhibited by (1S,3R)- and (1S,3S)-isomalathion. Comparison ofk+4values for hen brain AChE inhibited by each stereoisomer of isomalathion and isoparathion methyl corroborated that only the (1S)-isomalathions failed to produce the expectedO,S-dimethyl phosphoryl-conjugated enzymes. The results for (1R)-isomalathions suggest that the mechanism of inhibition of AChE by these isomers is the expected one involving diethyl thiosuccinyl as the primary leaving group. In contrast, the results for (1S)-isomalathions are consistent with an alternative mechanism of inhibition by these isomers implicating loss of thiomethyl as the primary leaving group.
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Details
- Title
- Kinetic Evidence for Different Mechanisms of Acetylcholinesterase Inhibition by (1R)- and (1S)-Stereoisomers of Isomalathion
- Creators
- Suree Jianmongkol - Toxicology Program, Department of Environmental & Industrial Health, School of Public Health, The University of Michigan, Ann Arbor, Michigan, 48109Brian R Marable - Toxicology Program, Department of Environmental & Industrial Health, School of Public Health, The University of Michigan, Ann Arbor, Michigan, 48109Clifford E Berkman - Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California, 94132Todd T Talley - Department of Chemistry, The University of Montana, Missoula, Montana, 59812Charles M Thompson - Department of Chemistry, The University of Montana, Missoula, Montana, 59812Rudy J Richardson - Toxicology Program, Department of Environmental & Industrial Health, School of Public Health, The University of Michigan, Ann Arbor, Michigan, 48109
- Publication Details
- Toxicology and applied pharmacology, Vol.155(1), pp.43-53
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Inc
- Identifiers
- 99900547676801842
- Language
- English
- Resource Type
- Journal article