A steric blockade model for inhibition of acetylcholinesterase by peripheral site ligands and substrate

Rosenberry, Terrone L.; Mallender, William D.; Thomas, Patrick J.; Szegletes, T.

doi:10.1016/s0009-2797(99)00017-4

Cited by 48 publications

(35 citation statements)

References 14 publications

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“…The black curve is the rate of input of ACH into the cleft, consistent with known rapid input [33,35]. Typical apparent K m values are in the range 50-100 mM [28,36,37]; we used the value 58 mM in the model [28]. The blue curve in Fig.…”

Section: C Reed Et Almentioning

confidence: 81%

“…This is exactly what occurs. The peak of the ACHe velocity curve occurs at about 1 mM [28]. The rise time of ACH release is less than 100 ms [26,33], and the concentration of ACH is quickly driven past 1 mM and rises to 10 mM and perhaps higher [32].…”

Section: C Reed Et Almentioning

confidence: 96%

“…Salpeter and coworkers [26,27] and Rosenberry and coworkers [28,29] have carried out detailed studies of the kinetics of ACH release, binding to post-synaptic receptors, and degradation by ACHe.…”

Section: C Reed Et Almentioning

confidence: 99%

“…A solution for this problem would be to have ACHe be inhibited by its substrate ACH so that when ACH is at high concentrations the degradation proceeds relatively slowly and then accelerates as the concentration drops. Substrate inhibition of ACHe by ACH was noticed as long ago as 1969 [31], but its functional importance has been emphasized only recently [28,32]. For this scenario to work, ACH should be released very rapidly into the cleft so that the concentration of ACH rises quickly into the inhibitory range.…”

Section: C Reed Et Almentioning

confidence: 99%

“…4A shows the ACH concentration in the cleft as a function of time if we assume simple Michaelis-Menten kinetics. The green curve shows the concentration of ACH in the cleft if substrate inhibition is added with K i ¼ 17 900 as determined experimentally [28]. In each case, the V max was the same and its value was chosen so that the concentrations in the cleft go over 10 mM.…”

Section: C Reed Et Almentioning

confidence: 99%

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The biological significance of substrate inhibition: A mechanism with diverse functions

2010

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Many enzymes are inhibited by their own substrates, leading to velocity curves that rise to a maximum and then descend as the substrate concentration increases. Substrate inhibition is often regarded as a biochemical oddity and experimental annoyance. We show, using several case studies, that substrate inhibition often has important biological functions. In each case we discuss, the biological significance is different. Substrate inhibition of tyrosine hydroxylase results in a steady synthesis of dopamine despite large fluctuations in tyrosine due to meals. Substrate inhibition of acetylcholinesterase enhances the neural signal and allows rapid signal termination. Substrate inhibition of phosphofructokinase ensures that resources are not devoted to manufacturing ATP when it is plentiful. In folate metabolism, substrate inhibition maintains reactions rates in the face of substantial folate deprivation. Substrate inhibition of DNA methyltransferase serves to faithfully copy DNA methylation patterns when cells divide while preventing de novo methylation of methyl-free promoter regions. Keywords:.b iological function; enzyme kinetics; substrate inhibitionThe kinetics of an enzymatic reaction are typically studied by varying the concentration of substrate and plotting the rate of product formation as a function of substrate concentration. In the conventional case this yields a typical hyperbolic Michaelis-Menten curve, and a linear reciprocal LineweaverBurk plot, from which the kinetic constants of the enzyme can be calculated. A surprisingly large number of enzymes do not behave in this conventional way. Instead, their velocity curves rise to a maximum and then decline as the substrate concentration goes up. This phenomenon is referred to as substrate inhibition, and it is estimated that it occurs in some 20% of enzymes [1]. A partial list of enzymes that show substrate inhibition appears in Box 1.Substrate inhibition is often interpreted as an abnormality that comes from using artificially high substrate concentration in a laboratory setting. In a review article on the mechanisms of substrate inhibition in 1994, Kuehl [2] commented that ''although recognized early on as an almost universal phenomenon, it has nevertheless met an almost universal disinterest. Probably the main reason for this neglect is that the majority of enzymologists and many authorities in the field regard substrate inhibition as being almost always a nonphysiological phenomenon.'' There are several reasons for suspecting that substrate inhibition is not a pathological phenomenon, but a biologically relevant regulatory mechanism. First, in many cases normal substrate concentrations are to the right of the velocity maximum, which indicates that these enzymes typically operate under substrate inhibition. Second, many enzymes have specialized sites where a second substrate molecule can bind and act as an allosteric inhibitor. For those enzymes, substrate inhibition is clearly a specially evolved property. Third, evidence is accumulating that substr...

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Section: C Reed Et Almentioning

confidence: 81%

Section: C Reed Et Almentioning

confidence: 96%

Section: C Reed Et Almentioning

confidence: 99%

Section: C Reed Et Almentioning

confidence: 99%

Section: C Reed Et Almentioning

confidence: 99%

See 3 more Smart Citations

The biological significance of substrate inhibition: A mechanism with diverse functions

2010

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Synthesis and Biological Evaluation of Tacrine‐Thiadiazolidinone Hybrids as Dual Acetylcholinesterase Inhibitors

Dorronsoro¹,

Alonso²,

Castro³

et al. 2005

Archiv der Pharmazie

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The synthesis of tacrine-thiadiazolidinone hybrids is described. These compounds are designed as dual acetylcholinesterase inhibitors binding simultaneously to the peripheral and catalytic sites of the enzyme. All tested compounds exhibit significant AChE inhibitory activity. Competition assays using propidium as reference of selective ligand for the peripheral anionic site on acetylcholinesterase indicates the influence of the designed compounds over the peripheral site. They can be considered as new leads in the optimization of Alzheimer's disease modifying agents.

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On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

Driant

Nachon²,

Ollivier

et al. 2017

ChemBioChem

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Acetylcholinesterase (AChE) is an enzyme of the serine hydrolase superfamily and a mediator of the signal transmission at cholinergic synapses catalysing acetylcholine cleavage into an acetate and a choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds. The covalent inhibition of AChE does not revert spontaneously and in order to restore catalytic activity known reactivator compounds have limited action. Simulations of VX-inhibited AChE reactivation by pralidoxime, a classical reactivator, were performed by QM/MM. These simulations allowed for a broader view of the effect of protonation states of active site residues. These calculations provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM was also explored in both protonation states of Glu202, showing that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Since the active site of serine hydrolases is highly conserved, this work shades new insights on the interplay between the triad residues of the catalytic center and this glutamate newly identified as protonatable.

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A steric blockade model for inhibition of acetylcholinesterase by peripheral site ligands and substrate

Cited by 48 publications

References 14 publications

The biological significance of substrate inhibition: A mechanism with diverse functions

The biological significance of substrate inhibition: A mechanism with diverse functions

Synthesis and Biological Evaluation of Tacrine‐Thiadiazolidinone Hybrids as Dual Acetylcholinesterase Inhibitors

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach

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