The arrangement of substrate and organophosphorus-inhibitor leaving groups in acetylcholinesterase active site

Abstract

The leaving groups of serine esterase substrates and organophosphorus inhibitors bind to different loci at the enzyme active site. Kinetic proof of this general conclusion is presented in the case of acetylcholinesterase reactions. The proposed model for acetylcholinesterase active site provides a new stereochemical mechanism for the phosphorylated enzyme reactivation.

Syntheses and spectroscopic characterization of some phosphoramidates as reversible inhibitors of human acetylcholinesterase and determination of their potency

“…Debord et al [37] showed that the (O)PN 3 moeity in aliphatic phosphoramides interacts with the hydrophilic zone of the catalytic site of butyrylcholinesterase. Jarv et al indicated [38] that in acetylcholinesterase three hydrophobic regions bind to hydrocarbon substituents and surround this zone. In phosphoramide 2, the existence of two nitroaniline groups decrease the lipophilicity of the aromatic ring.…”

Biochemical Pharmacology

“…Because the geometry of nucleophilic attack at a carbonyl carbon atom (present in the substrate and in carbamates) differs from that of nucleophilic attack at a tetrahedral phosphorus atom, Järv, J. et al (1977) took the view that, if the serine OH were to be relatively fixed, it would not be possible for the leaving groups in these molecules to occupy the same region of the enzyme active site. These authors compared data on the rate of enzyme-catalysed hydrolysis of acetate esters (CH3COOR, where R is a simple alkyl group) with results for the rate of reaction with analogous phosphonates (RO) (CH 3 ) P(0)(SC 4 H 9 ).…”

Study of the relationship between spatial structure and anticholinesterase activity of o-phosphorylate oximes

“…However the question of what is the binding site of the remote group of an organophosphorus inhibitor at the active center of ACE is still under discussion. In particular, it was demonstrated [19] that substituents R in the molecules ofsubstrates CH3C(O)OR and ACE inhibitors (RO)CH3P(O)SC4H 9 interact with the same locus Pl in the active center of the enzyme (see scheme in Fig. 5), so that the remote group of the inhibitor (in this vase SC4H9) is bound at the locus P3 of the active center of ACE, rather than at the anionic site.…”

“…This result suggests that a high activity of the compounds is provided by electronegative substituents, which implies that the active center of the enzyme must contain groups capable of retaining these electronegative fragments. [19]; P i and P2 are the regions of binding of the remote group X and the awl part of the substrate, respectively; P3 is the region of binding the remote group X of the organophosphorus inhibitor.…”