Acetylcholinesterase stereoselectivity

The P-atom in sarin (9.84), soman (9.85), and tabun (9.87) is a stereogen-ic center, allowing for stereoselective enzymatic hydrolysis [162], This aspect has been extensively investigated for soman, which exists as four stereoisomers by virtue of the presence of a second stereogenic center (C-atom). These stereoisomers are usually designated as C(+)P(-), C(-)P(+), C(+)P(+), and C(-)P(-), where C(+/-) refers to the 1,2,2-trimethylpropyl moiety and P(+/ ) to the P-atom. Such a nomenclature may be convenient but has no implication for the absolute configuration. The C(+)P( ) and Cf-)P(-) epimers are the more active toward acetylcholinesterase and, hence, the more toxic ones. In contrast, the C(+)P(+) and C(-)P(+) epimers are preferentially hydrolyzed... 

J. R. Grothusen, T. M. Brown, Stereoselectivity of Acetylcholinesterase, Arylester Hydrolase, and Chymotrypsin toward 4-Nitrophenyl Alkyl(phenyl)phosphinates , Pestic. Biochem. Physiol. 1986, 26, 100-106. 

Doom, J.A., Talley, T.T., Thompson, C.M., Richardson, R.J. (2001a). Probing the active sites of butyrylcholinesterase and cholesterol esterase with isomalathion conserved stereoselective inactivation of serine hydrolases stmcturally related to acetylcholinesterase. Chem. Res. Toxicol. 14 807-13. 

Of particular interest is the study of the biological mechanisms associated with enzyme stereoselectivity and enantioselectivity. For example, MD simulations have been successful in explaining the different affinities of trypsin and acetylcholinesterase to the diastereomers of soman inhibitors [154] and the ability of subtilisin Carlsberg and a-chymotrypsin to discriminate between R-and S- configurations of chiral aldehyde inhibitors [155, 156]. 

Hsung 2 used a [4 4-2] cycloaddition reaction of a y-pyrone to synthesize the tetracyclic core of arisugacin, a novel inhibitor of acetylcholinesterase. He noticed an unexpected concentration effect on the stereoselectivity in the reactions of 3-cyano-/-benzopyrone derivatives with electron-rich dienes. When 1-methoxybutadiene (187) reacted with /-benzopyrone 188, for example, the ratio between endo adduct 189 and exo adduct 190 depended on the concentration of 188, as demonstrated by the data given in Table 4 (equation 52). Raising the concentration of 188, while keeping the diene concentration twice as high, caused the reaction to become less endo selective. Variation of the diene concentration, while keeping the /-benzopyrene concentration constant, did not demonstrate a clear trend. 

Addition of methyl groups to either one or both of the ethylene carbons results in chiral molecules. Muscarinic receptors (see below) display stereoselectivity for the enantiomers of methacholine. The S-(+)-enantiomer is equipotent with acetylcholine, and the R-(-)-enantiomer is approximately 20-fold less potent. Acetylcholinesterase hydrolyzes the S-(+)-isomer much slower (approximately half the rate) than acetylcholine. The R-(-)-isomer is not hydrolyzed by AChE and even acts as a weak competitive inhibitor of the enzyme. This stability toward AChE hydrolysis as well as the AChE inhibitory effect of the R-(-)-enantiomer may explain why racemic methacholine produces a longer duration of action than acetylcholine. The nicotinic receptor and AChE exhibit little stereoselectivity for the optical isomers of acetyl-a-methylcholine. 

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