API

Stressor: 80

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N-methyl Carbamates

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Acetylcholinesterase (AchE) Inhibition

Carbamates trigger AChE inhibition through electrostatic interactions at the enzyme’s anionic site and binding with the serine hydroxyl group at the esteratic site (Wilson 2010; Fukuto 1990). Carbamates, which were originally based on the plant alkaloid physostigmine, attach to the AChE via a ‘reversible’ carbamylation. Note that the use of the term ‘reversible’ relates to the relative rate at which the carbamylation occurs since acetylcholine and carbamates both form covalent bonds with the enzyme. Certain steric and electronic requirements, as well as the leaving group on the pesticide, are critical to the likelihood that the methyl-carbamate will inhibit AChE (See Figure).  

Metabolism also plays a role in the potency of some carbamates.  Select procarbamates require metabolism to form an active AChE inhibitor (e.g., carbosulfan must be metabolized to carbofuran), or are made more potent via metabolism (e.g., aldicarb oxidation to the more toxic sulfoxide form) (Sogob and Vilanova 2002; Stenersen 2004). 


 

Base Structure (Carbamate)

Configuration

R1: Methyl group

R2:  Hydrogen group;

XR3:  Leaving group that is an aryloxy or oxime;

pKa:  For oxime and substituted phenols, a pKa in the range of 10 ensures carbamylation;

Carbamates must ‘fit’ in the enzyme active site to be effective inhibitors

 




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