1995
DOI: 10.1021/bi00036a028 View full text |Buy / Rent full text
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Abstract: We have examined the specificity of planar carboxyl and tetrahedral phosphonyl esters for mouse cholinesterases and have delineated the orientation of these ligands in the enzyme active center. The approach involved altering acyl pocket dimensions by site-specific mutagenesis of two phenylalanines and varying ligand size and enantiomer presentation. Substrate catalysis rates by wild type acetylcholinesterase (AChE) of acetyl-, butyryl-, and benzoylthiocholine diminished with increasing size of the acyl moiety.… Show more

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“…Consequently, unlike TcAChE, hBChE does not exert stereoselectivity for OP bearing small substituents. This is the case for sarin (methyl and isopropyloxy groups) and VX (methyl and ethoxy groups) (23). hBChE can react with both stereoisomers of sarin or VX, while TcAChE reacts preferentially with the stereoisomer that yields the smallest substituent in the acylbinding pocket.…”
Section: Mechanism Of Aging By Breaking P-o Bondmentioning
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rupbmjkragerfmgwileyiopcupepmcmbcthiemesagefrontiersapsiucrarxivemeralduhksmucshluniversity-of-gavle
“…Consequently, unlike TcAChE, hBChE does not exert stereoselectivity for OP bearing small substituents. This is the case for sarin (methyl and isopropyloxy groups) and VX (methyl and ethoxy groups) (23). hBChE can react with both stereoisomers of sarin or VX, while TcAChE reacts preferentially with the stereoisomer that yields the smallest substituent in the acylbinding pocket.…”
Section: Mechanism Of Aging By Breaking P-o Bondmentioning
“…Because the absolute stereochemistry of the methylphosphonates is known (29), the chiral S p methylphosphonates will direct their phosphonyl oxygen toward the oxyanion hole, the small methylphosphonyl moiety will be directed to the acyl pocket, and the more bulky alkoxy group directed to choline binding site (30). For the three S p enantiomers, very little or no change in emission maxima for acrylodan at positions 124, 262, and 287 is discerned.…”
Section: Ligand-specific Conformation Of Acetylcholinesterase 43304mentioning
“…R p alkyl methylphosphonates react far more slowly with the enzyme than the S p enantiomers (30), and we use formation of the (R p )-3,3-dimethylbutyl methylphosphonyl enzyme as an example. Formation of initial reversible complex can be detected by an immediate reduction in quantum yield of acrylodan at 81 with little change in emission maximum (Fig.…”
Section: Ligand-specific Conformation Of Acetylcholinesterase 43304mentioning
“…In BChE, these Phe are replaced by smaller residues (Leu, Ile or Val), resulting in a more spacious acyl pocket, capable of accommodating larger groups such as butanoyl or benzoyl. 25,66 Mutagenesis experiments showed that mouse AChE with the mutations Phe295Leu and Phe297Ile loses its specificity and reduces its maximum catalytic rate (k cat ), which leads to the conclusion that these residues are important for substrate stabilization at the optimal catalysis position. 25 Moreover, mutations Phe297Ile and Phe297Val change the kinetic profile of AChE from one of substrate-inhibition to another of substrate-activation analogous to that of BChE.…”
Section: Ache Active Sitementioning
“…It is believed that the phenylalanine residues in the acyl pocket (mainly Phe-290 in TcAChE) are the major agents of this selectivity, due to the steric constraints imposed by them. 66,118 However, molecular modeling 97 and mutagenesis studies 63,119 have shown that the oxyanion hole, the anionic subsite and the peripheral anionic site also play an important role in stabilization of the phosphyl-AChE complex and in stereoselectivity. For nerve agents, the stereoisomer with the absolute configuration shown in Figure 9 is usually the most active AChE inhibitor, since the R'O group is greater than the R group.…”
Section: Opcs As Chemical Warfare Agentsmentioning