PMID: 11904227Mar 21, 2002Paper

Substrate activation in acetylcholinesterase induced by low pH or mutation in the pi-cation subsite

Biochimica Et Biophysica Acta
Patrick MassonOksana Lockridge

Abstract

Substrate inhibition is considered a defining property of acetylcholinesterase (AChE), whereas substrate activation is characteristic of butyrylcholinesterase (BuChE). To understand the mechanism of substrate inhibition, the pH dependence of acetylthiocholine hydrolysis by AChE was studied between pH 5 and 8. Wild-type human AChE and its mutants Y337G and Y337W, as well as wild-type Bungarus fasciatus AChE and its mutants Y333G, Y333A and Y333W were studied. The pH profile results were unexpected. Instead of substrate inhibition, wild-type AChE and all mutants showed substrate activation at low pH. At high pH, there was substrate inhibition for wild-type AChE and for the mutant with tryptophan in the pi-cation subsite, but substrate activation for mutants containing small residues, glycine or alanine. This is particularly apparent in the B. fasciatus AChE. Thus a single amino acid substitution in the pi-cation site, from the aromatic tyrosine of B. fasciatus AChE to the alanine of BuChE, caused AChE to behave like BuChE. Excess substrate binds to the peripheral anionic site (PAS) of AChE. The finding that AChE is activated by excess substrate supports the idea that binding of a second substrate molecule to the PAS induces a con...Continue Reading

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Citations

Mar 30, 2006·Parasitology·M E SelkirkJ B Matthews
Feb 28, 2003·European Journal of Biochemistry·Patrick MassonOksana Lockridge
Jan 15, 2005·Free Radical Biology & Medicine·Carol A BallingerEdward M Postlethwait
Feb 13, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Miroslav Pohanka, Ondrej Holas
Mar 8, 2006·The FEBS Journal·Anna HrabovskáPatrick Masson
Nov 18, 2014·TheScientificWorldJournal·Mohd Khalizan SabullahSiti Aqlima Ahmad
Feb 11, 2005·Biochemistry. Biokhimii︠a︡·Ju P VainonenS M Avaeva
Apr 14, 2016·The Journal of Physical Chemistry. B·Tal EinavRob Phillips
Dec 23, 2003·European Journal of Biochemistry·Patrick MassonLawrence M Schopfer
Oct 16, 2015·Nature Communications·Iris GrossmanDeborah Fass
Apr 18, 2019·Protein Science : a Publication of the Protein Society·Stephanie M BesterScott D Pegan
Aug 27, 2013·The Journal of Biological Chemistry·Marina BesprozvannayaBriana M Burton
Jun 28, 2019·Chemico-biological Interactions·Aliya R MukhametgalievaPatrick Masson
Dec 22, 2006·Biochimica Et Biophysica Acta·Patrick MassonLawrence M Schopfer

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