Specificity and orientation of trigonal carboxyl esters and tetrahedral alkylphosphonyl esters in cholinesterases

Biochemistry
N A HoseaP Taylor

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. In contrast, substitution of the acyl pocket phenylalanines giving the mutants F295L and F297I of AChE yielded more efficient catalysis of the larger substrates and a specificity approaching that of butyrylcholinesterase. Extension from planar substrates to enantiomerically pure organophosphonates allowed for an analysis of enantiomeric selectivity. We found that AChE reactions are 200-fold faster with the Sp than the Rp enantiomer of of cycloheptyl methylphosphonyl thiocholine. Upon the acyl pocket size being enlarged, the Rp enantiomer became more reactive while reaction with the Sp enantiomer was slightly reduced. In fact, the F297I mutant displayed inverted stereospecificity. A visual correlation with the kinetic data...Continue Reading

Citations

Mar 21, 2002·Biochimica Et Biophysica Acta·Patrick MassonOksana Lockridge
Jul 29, 2000·Bioorganic & Medicinal Chemistry Letters·J R SaltmarshC M Thompson
Jun 15, 2011·Chemical Reviews·Kibong KimDavid G Churchill
Nov 16, 2011·Journal of the American Chemical Society·Perrin Baker, Stephen Y K Seah
Feb 28, 2003·European Journal of Biochemistry·Patrick MassonOksana Lockridge
Jun 28, 2011·Arhiv za higijenu rada i toksikologiju·Anita BosakZrinka Kovarik
Oct 5, 2007·Arhiv za higijenu rada i toksikologiju·Palmer TaylorZoran Radić
Feb 20, 2014·The Journal of Physical Chemistry. a·Ibon AlkortaJanet E Del Bene
Dec 15, 2015·Chemical Reviews·Yoon Jeong JangDavid G Churchill
Feb 2, 2010·Analytica Chimica Acta·Ravi SinhaLia Stanciu
May 13, 2008·Chemico-biological Interactions·Avigdor ShaffermanArie Ordentlich
Jul 10, 2003·Biochemical and Biophysical Research Communications·Takeshi NabeshimaYoshiaki Kono
Apr 7, 2006·Biochemical and Biophysical Research Communications·Zrinka KovarikPalmer Taylor
Dec 22, 2006·Biochimica Et Biophysica Acta·Patrick MassonLawrence M Schopfer
Jan 31, 2006·Biomolecular Engineering·Silvana Andreescu, Jean-Louis Marty
Jan 3, 2008·Archives of Biochemistry and Biophysics·Anita BosakZrinka Kovarik
Nov 18, 2005·Chemico-biological Interactions·Arie OrdentlichAvigdor Shafferman
Jan 15, 2014·Materials Science & Engineering. C, Materials for Biological Applications·Yongjun LiuLong Yang
Aug 19, 2007·Journal of Medical Entomology·I V Coutinho-AbreuJ M Ramalho-Ortigão
Jul 25, 1998·The Journal of Biological Chemistry·A OrdentlichA Shafferman
Dec 7, 2007·The Journal of Pharmacology and Experimental Therapeutics·Bin LiOksana Lockridge
May 20, 2009·The Journal of Physical Chemistry. B·Reinaldo T Delfino, José D Figueroa-Villar
Nov 11, 2009·Langmuir : the ACS Journal of Surfaces and Colloids·Yu-Ho WonLia A Stanciu

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