Acetylcholinesterase, structure

FIGURE 10.3 Acetylcholinesterase structure of catalytic triad. The structure of the catalytic triad of the active center of the enzyme is shown (from Sussman et al. 1991). 

Kang SY, Lee KY, Sung SH, Park MJ, Kim YC, Coumarins isolated from Angelica gigas inhibit acetylcholinesterase Structure-activity relationships, f Nat Prod 64 683-685,2001. 

Worek F et al Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes. Biochem Pharmacol 2004 68 2237. [PMID 15498514]... 

Fig 5-2. This schematic ribbon diagram shows the structure of Torpedo californica acetylcholinesterase. The diagram is color-coded green the 537-amino acid polypeptide of the enzyme monomer pink the 14 aromatic residues that line the deep aromatic gorge leading to the active site and gold and blue a model of the natural substrate for acetylcholinesterase, the neurotransmitter acetylcholine, docked in the active site. Reprinted with permission from Sussman JL, Silman I. Acetylcholinesterase Structure and use as a model for specific cation-protein interactions. Curr Opin Struct Biol. 1992 2 724. 

Maxwell DM, Brecht KM. 1992. Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analougues of organophosphorus compounds. Chem Res Toxicol 5 66-71. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Devonshire, A.L., Byrne, G.D., and Moores, G.D. et al. (1998). Biochemical and molecular characterisation of insecticide sensitive acetylcholinesterase in resistant insects. In Structure and Function of Cholinesterases and Related Proteins, Doctor, B.P, Quinn, D.M., Rotundo, R.L. and Taylor, P. (Eds.) New York Plenum Press, 491 96. 

Sussman, J.L., Harel, M., and Frolow, F. et al. (1991). Atomic structure of acetylcholinesterase from Torpedo califomica a prototypic acetylcholine-binding protein. Science 253, 872-879. 

Both the G- and V-agents have the same physiological action on humans. They are potent inhibitors of the enzyme acetylcholinesterase (AChE), which is required for the function of many nerves and muscles in nearly every multicellular animal. Normally, AChE prevents the accumulation of acetylcholine after its release in the nervous system. Acetylcholine plays a vital role in stimulating voluntary muscles and nerve endings of the autonomic nervous system and many structures within the CNS. Thus, nerve agents that are cholinesterase inhibitors permit acetylcholine to accumulate at those sites, mimicking the effects of a massive release of acetylcholine. The major effects will be on skeletal muscles, parasympathetic end organs, and the CNS. 

Taylor P, Li Y, Camp S, et al. 1993. Structure and regulation of expression of the acetylcholinesterase gene. Chem Biol Interactions 87 199-207. 

Arpagaus, M., Fedon, Y., Cousin, X., Chatonnet, A., Berge, J.-B., Fournier, D. and Toutant, J.-P. (1994) cDNA sequence, gene structure, and in wire expression of ace-1, the gene encoding acetylcholinesterase of class A in the nematode Caenorhabditis elegans. Journal of Biological Chemistry 269, 9957-9965. 

Bourne, Y., Taylor, P. and Marchot, P. Acetylcholinesterase inhibition by fasciculin. Crystal structure of the complex. Cell 83 503-512,1995. 

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