Abstract
The principal biological role of acetylcholinesterase (AChE, acetylcholine hydrolase, EC 3.1.1.7) is to terminate signal transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter, acetylcholine (ACh) (Barnard, 1974). In keeping with this requirement, AChE possesses a remarkably high specific activity, especially for a serine hydrolase (Quinn, 1987), functioning at a rate approaching that of a diffusion-controlled reaction (Bazelyansky et al., 1986). Early kinetic studies indicated that the active site of AChE consists of two subsites, the ‘esteratic’ and ‘anionic’ subsites, corresponding to the catalytic machinery and the choline-binding pocket, respectively (Nachmansohn and Wilson, 1951). A second, ‘peripheral’, anionic site exists, so named because it appears to be distant from the active site (Taylor and Lappi, 1975). The elucidation of the three-dimensional structure of Torpedo AChE (Sussman et al., 1991) served to confirm these earlier studies, and has showed that AChE contains a catalytic triad similar to that present in other serine hydrolases (Steitz and Shulman, 1982). Unexpectedly, it also revealed that this triad is located near the bottom of a deep and narrow cavity, ∼20 Å deep, which has been named the ‘active-site gorge’. The cavity is lined by the rings of fourteen aromatic residues which are conserved in the AChE sequences published so far (Gentry and Doctor, 1991). Much of the subsequent research on structure-function relationships in AChE has been concerned with the functional significance of the gorge and with the role of the aromatic rings which account for more than 50% of its surface area (Axelsen et al., 1994). Thus, structural evidence (Axelsen et al., 1994; Sussman et al., 1991), as well as evidence obtained by modeling (Harel et al., 1992), by chemical modification (Harel et al., 1993; Schalk et al., 1992; Weise et al., 1990), and by site-directed mutagenesis (Harel et al., 1992; Ordentlich et al., 1993; Radie et al., 1993; Shafferman et al., 1992; Vellom et al., 1993), all point to important roles for certain of these conserved aromatic residues in both the ‘esteratic’ and ‘anionic’ subsites of the active site, and in the ‘peripheral’ anionic site.
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Sussman, J.L., Harel, M., Raves, M., Quinn, D.M., Nair, H.K., Silman, I. (1995). Structures of Complexes of Acetylcholinesterase with Covalently and Non-Covalently Bound Inhibitors. In: Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P. (eds) Enzymes of the Cholinesterase Family. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1051-6_15
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DOI: https://doi.org/10.1007/978-1-4899-1051-6_15
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