Peripheral anionic site

The anionic subsite (Ttp 84 and Phe 330) lies between the peripheral and acylation sites, halfway down the gorge and accommodates the positively charged quaternary ammonium of the choline moiety. Ttp 84 orients the charged part of the substrate to the active centre. This subsite is involved in a cross-talk mechanism with the peripheral anionic site (PAS) [3]. 

Choudhary MI, Nawaz SA, Zaheer-ul-Haq Azim MK, cr 7/.,Juhflorine, A potent natural peripheral anionic-site-binding inhibitor of acetylchoflnesterase with calcium-channel blocking potential, a leading candidate for Alzheimer s disease therapy, Biochem Biophys Res Comm 332 1171—1179, 2005. 

Bourne, Y., Taylor, P., Radic, Z., March-ot, P. Structural Insights into Ligand Interactions at the Acetylcholinesterase Peripheral Anionic Site. EMBO J. 2003, 22, 1-12. 

Other reversible inhibitors, such as propidium and the peptide toxin fasciculin, bind to the peripheral anionic site on AChE. This site resides at the lip of the gorge and is defined by tryptophan 286 and tyrosines 72 and 124 (Taylor, 2001). 

Fasciculin inhibition of AChE is prevented by chemical modification of the enzyme at a peripheral site (Duran et al, 1994). The specific interaction of fasciculin 2 with peripheral sites present in Electrophorus electricus AChE Ki, 0.04 nM fasciculin) was investigated by chemical modification with A,A-dimethyl-2-phenylaziridium (DPA) in the presence of active or peripheral anionic site protective agents. An enzyme was obtained that compared to the native AChE and was 10 times less sensitive to fasciculin 2. This enzyme was fully inhibited by edrophonium and tacrine, and was 25-170 times less sensitive to several peripheral site ligands. It seems fasciculin 2 binding to an AChE peripheral site partially overlaps the site of other peripheral site ligands including acetylcholine. 

Johnson, G., Moore, S.W. (2003). Human acetylcholinesterase binds to mouse laminin-1 and human collagen IV by an electrostatic mechanism at the peripheral anionic site. Neuro-sci. Lett. 337 37-40. 

The second anionic site of AChE, the so-called peripheral anionic site, is located at the active center gorge entry, and encompasses overlapping binding sites for different... 

Lin G, Lai CY, Liao WC. Molecular recognition by acetylcholinesterase at the peripheral anionic site Structure-activity relationships for inhibitions by aryl carbamates. Bioorg Med Chem 1999 7 2683-9. 

A series of novel l, 3-dihydroxyxanthone Mannich base derivatives were synthesized, structure elucidated, and evaluated for anticholinesterase activity. Most of the target compounds exhibited moderate to good inhibitory activities with the IC50 values at micromole level concentration against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, 2 - ((diethylamino )methyl) -1 -hydroxy- 3 - (3 -methylbut-2-enyloxy) -9H-xanthen-9-one showed potent inhibitory activity against AChE and the best inhibitory activity against BuChE. The Mannich base derivatives were likely to bind to the active site (AS) and the peripheral anionic site (PAS) of cholinesterases [169]. 

D. Synaptic Acetylcholinesterase and Butyrylcholinesterase Have High Homology BUT Distinct Peripheral Anionic Sites and C Termini... 

The action of OP nerve agents on the nervous system results from their effects on enzymes, particularly esterases. The most notable of these esterases is acetylcholinesterase. The active site of acetylcholinesterase comprises a catalytic triad of serine, histidine and glutamic acid residues and other important features of the enzyme are a gorge connecting the active site to the surface of the protein and a peripheral anionic site (Bourne etal., 1995,1999 Sussman etal., 1991 Thompson and Richardson, 2004), The OPs phosphy-late1 the serine hydroxyl group in the active site of the enzyme. 

For many decades, it has been thought that the interactions of the anticholinesterase OP and CM compounds with AChE and BuChE are kinctically analogous to those of ACh. In the absence of binding of ACh to the peripheral anionic site of AChE (the validity of this assumption is discu.s.sed later), hydrolysis of ACh by AChE or BuChE can be de,scribed by a Ping Pong Bi Bi kinetic scheme (Fig. 5). In this scheme, ACh represents the first substrate, whereas water represents the second. Additionally, choline is the first product formed, and it is released before the second... 

Note that the kinetic interactions of substrates with AChE and BuChE are in reality more complex than portrayed in Fig. 5. Both cholinesterases have been shown to display substrate inhibition and activation, depending on the incubation condilion.s (Masson et ai., 2004). probably as a result of the presence of a binding site separate from the active site, termed the peripheral anionic site (Changeux. 1966 Taylor and Radic, 1994 Barak et ai., 1995 Soreq and Seidman,... 

Although the acyl pocket is critical in determining the fit of OPs into the active site gorge, Ordentlich et al. (2004) documented the importance of the peripheral anionic site, as well as several additional sites, in determining the stereoselectivity of AChE toward enantiomers of methylphosphonates. 

Ordentlich, A., Barak, D., Sod-Moriah, G., Kaplan, D., Mizrahi, D Segall, Y.. Kronman, C, Karton, Y., Lazar, A., Marcus, D, Velan, B.. and Shatferman, A. (2004). Stereoselectivity toward VX is determined by interactions with residues of the acyl pocket as well as of the peripheral anionic site of AChE, Biochemiury A3,11255-11265. 

John.son, G., and Moore, S, W, (1999). The adhesion function on acetylcholinesterase is located at the peripheral anionic site. Btochem. Biophys Res, Commun. 258, 758-762. 

Rl. Radio, Z., Reiner, E., and Taylor, P., Role of the peripheral anionic site on acetylcholinesterase Inhibition by substrates and coumarin derivatives. Mol. Pharmacol. 39, 98-104 (1991). 

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