Cholinesterases structure

Massoulie, J and Toutant, J. P (1988) Vertebrate cholinesterases structure and types of interactions, in Handbook of Experimental Pharmacology (Whitaker, V P, ed ), Sprmger-Verlag, Berlin, pp 167-224. 

Maxwell, D.M., Wolfe, A. D., Ashani, Y., Doctor, B.P. (1991). Cholinesterases and carboxylesterases as scavengers for organophosphorus agents. In Cholinesterases Structure, Function, Mechanism, Genetics and Cell Biology (J. Massou-lie, F. Bacon, E. Barnard, A. Chatonnet, B.P. Doctor, D.M. Quinn, eds), pp. 206-9. American Chemical Society, Washington. 

Studies of cholinesterase structure and the biological mechanisms of inhibition are necessary for effective drug development. Medicinal compounds like Ortho-7, Dibucaine, and HI-6 are predicted as good targets for modeled AChE and BChE proteins based on docking studies [172],... 

To date, 61 cholinesterase structures have been deposited in the Protein Data Bank. Forty are of T. califomica AChE, nine of mouse AChE, three of Drosophila AChE, two of human AChE, and seven of human BuChE. Overlaying of al Torpedo AChE structures reveals exceptional similarity in their protein backbone (Fig. 3A) and even in their side chain conformations (Fig. 3B). The mean value of the root mean square (RMS) deviation of the 40 Torpech AChE structure.s from the alpha carbon trace of the highest resolution (1.8 A), unligandcd Ica5 structure is only 0.26 iO. 10 A. Twelve... 

Maxwell DM, Wolfe AD, Ashani Y, Doctor BP. Cholinesterase and carboxylesterase as scavengers for organophosphorus agents. In Massoulie J, Bacou F, Barnard E, Chatonnet A, Doctor B, Quinn DM, eds. Cholinesterases Structure, Function, Mechanism, Genetics, and Cell Biology. Washington, DC American Chemical Society 1991 206-209. 

Therapeutic Function Cholinesterase reactivator (antidote for nerve gas) Chemical Name 2-[(Hydroxyimino)methyl] -1-methylpyridinium chloride Common Name 2-PAM chloride Structural Formula ... 

The Structure of the Active Surface of Cholinesterases and the Mechanism of Their Catalytic Action in lister Hydrolysis... 

Cholinesterases (ChEs), polymorphic carboxyles-terases of broad substrate specificity, terminate neurotransmission at cholinergic synapses and neuromuscular junctions (NMJs). Being sensitive to inhibition by organophosphate (OP) poisons, ChEs belong to the serine hydrolases (B type). ChEs share 65% amino acid sequence homology and have similar molecular forms and active centre structures [1]. Substrate and inhibitor specificities classify ChEs into two subtypes ... 

Monoamine Oxidases and their Inhibitors. Figure 2 Structures of MAO inhibitors. In the top row, the structural similarity between selegiline/L-deprenyl and methamphetamine is shown. Below are the aminoindan series of propargylamine compounds such as rasagiline. Next, the bifunctional MAO and cholinesterase inhibitors (ladostigil) and lastly, the iron chelator-MAO inhibitors. 

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. 

Neely WB. The use of molecular orbital calculations as an aid to correlate the structure and activity of cholinesterase inhibitors. Mol Pharmacol 1965 1 137-44. 

Before discussing the structure of the neurotoxins, it is necessary to define the types of neurotoxins. Three types of neurotoxins have been found so far in snake venoms. The first one is a postsynaptic neurotoxin, the second is a presynaptic neurotoxin, and the last is a cholinesterase inhibiting neurotoxin. Most sea snake venoms seem to contain only the postsynaptic neurotoxin. Only in Enhydrina... 

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 pmol/mg) just as ACh is at the neuromuscular junction. 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

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. 

A smouldering bag in a pesticide warehouse, believed to be of this, led to an explosion, killing three firemen, and fire which took six days to extinguish (possibly because of caution concerning anti-cholinesterase toxicity). This is a moderately high energy compound by virtue of the triazene function. Other pesticides present were of less energetic structure. 

Fig. 11.2. Schematic representation of the primary structure of secreted AChE B of N. brasiliensis in comparison with that of Torpedo californica, for which the three-dimensional structure has been resolved. The residues in the catalytic triad (Ser-His-Glu) are depicted with an asterisk, and the position of cysteine residues and the predicted intramolecular disulphide bonding pattern common to cholinesterases is indicated. An insertion of 17 amino acids relative to the Torpedo sequence, which would predict a novel loop at the molecular surface, is marked with a black box. The 14 aromatic residues lining the active-site gorge of the Torpedo enzyme are illustrated. Identical residues in the nematode enzyme are indicated in plain text, conservative substitutions are boxed, and non-conservative substitutions are circled. The amino acid sequence of AChE C is 90% identical to AChE B, and differs only in the features illustrated in that Thr-70 is substituted by Ser.

Cholinesterases secreted by parasitic nematodes of (predominantly) the alimentary tract or other mucosal tissues are authentic AChEs when analysed by substrate specificity, inhibitor sensitivities and primary structure. In the first two respects, they resemble vertebrate AChEs, whereas somatic (and therefore presumably neuronal) enzymes of nematodes analysed to... 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

The primary and tertiary structures of the cholinesterases are known. The primary structures of the cholinesterases initially defined a large and functionally eclectic superfamily of proteins, the a,P hydrolase fold family, that function not only catalytically as hydrolases but also as surface adhesion molecules forming heterologous cell contacts, as seen in the structurally related proteins... 

Seto, Y. and T. Shinohara. 1988. Structure-activity relationship of reversible cholinesterase inhibitors including paraquat. Arch. Toxicol. 62 37-40. 

Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schonenberger B, Deshpande SS. Structure-activity relationship of reversible cholinesterase inhibitors activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex. Braz. J. Med. Biol. Res. 21 1173-1196, 1988. 

While nerve agents vary in molecular structure, they all exert the same physiological effect on the body an increase in acetylcholine throughout the body caused by interference with a vital enzyme known as cholinesterase. The four primary nerve agents are tabun, sarin, soman, and VX. 

With D.F.P., the reaction was far more difficult and this led Wilson to combine the hydroxylamino group with a suitably placed N structure in the same molecule. Oximes will also restore activity of poisoned cholinesterase.8... 

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