Acetylcholinesterase acceleration

Barnett, P., Rosenberry, T.L. (1977). Catalysis of acetylcholinesterase acceleration of the hydrolysis of neutral acetic acid esters by certain aromatic cations. J. Biol. Chem. 252 7200-6. Benz, R.D. (2007). Toxicological and clinical computational analysis and the US FDA/CDER. Expert Opin. Drug Metab. Toxicol. 3 109-24. 

Inestrosa, N.C., Alvarez, A., Perez, C.A., Moreno, R.D., Vicente, M., Linker, C., Casanueva, O.I., Soto, C., Garrido, J. (1996). Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer s fibrils possible role of the peripheral site of the enzyme. Neuron 16 881-91. 

Even more reactive towards acetylcholinesterase are the organophosphorus derivatives developed as chemical warfare nerve agents, e.g. sarin. Such compounds react readily with the enzyme and form very stable addition intermediates. It is unusual to see fluoride as a leaving group, as in sarin, but its presence provides a huge inductive effect, thus accelerating the initial nucleophilic addition step (see also Section 13.7). 

Petrali, J. P., and Mills, K. R. 2001. Microwave-assisted cytochemistry Accelerated visualization of acetylcholinesterase at motor endplates. In Microwave Techniques and Protocols (R.T. Giberson and R.S. Demaree, eds.), pp. 265-172. Humana Press, Totowa NJ. 

Luo C, Ashani Y and Doctor BP (1998a). Acceleration of oxime-induced reactivation of organophosphate -inhibited fetal bovine serum acetylcholinesterase by monoquaternary and bisquaternary ligands. Mol Pharmacol, 53, 718-726. 

Enzymes accelerate the attainment of equilibrium of chemical reactions by a factor of 10 -10 as compared with uncatalyzed reactions. Several enzymes, e.g., catalase, acetylcholinesterase, and fumarase, have achieved virtual catalytic perfection approaching the diffusion-controlled limit. Thus, the splitting of H2O2 is accelerated by a factor of 3 x 10 in the presence of catalase. 

In Brownian dynamics simulations, electrostatic steering of the substrate toward the enzyme s active site(s) is generally, observed to increase the association rate over that for an uncharged model system without electrostatic interactions by one to two orders of magnitude. This increase is primarily due to electrostatic complementarity between the substrate and the enzyme active site (and access channel, if applicable). Thus rate acceleration can even be achieved when both the enzyme and the substrate have net charges of the same sign. This is also true when the rates are mostly rather insensitive to point mutations in the enzyme that are far from the active site (see e.g., simulations of acetylcholinesterase mutants ). 

Acetylcholinesterase has also been shown to be Increased by a de novo Induced synthesis by actlnomycln D. This synthesis of acetylcholinesterase is Inhibited by puronycln and 5-fluororotlc acid. Acetylcholinesterase activity can be accelerated with acetyl fluoride In the presence of acetylcholine. 

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