Territrem B, a Tremorgenic Mycotoxin That Inhibits Acetylcholinesterase with a Noncovalent yet Irreversible Binding Mechanism

Abstract

Territrem B (TRB) is a fungal metabolite isolated fromAspergillus terreus shown previously to be a potent and irreversible inhibitor of acetylcholinesterase (AChE). In the present study, a number of binding and inhibition assays were carried out to further characterize the inhibitory effect of TRB. The results indicate that the binding of TRB (a) is much more selective than a well characterized selective inhibitor of AChE, BW284C51, (b) adopts a one-to-one stoichiometry with the enzyme, (c) cannot be undone by an AChE-regenerating oxime agent, which contrasts the ability of 8 M urea to release AChE-bound TRB, (d) is enhanced by high concentration NaCl but prevented, unless preincubated, by Triton X-100, and (e) exhibits quasi-first order kinetics with an overall inhibition constant of 0.01 nM ؊1 min ؊1 . Together these results suggest a very different irreversible binding (a noncovalent type) from that of the covalent type, which involves typical irreversible AChE inhibitors such as diisopropylfluorophosphate and neostigmine. According to the prediction of a molecular modeling study, the distinct AChE inhibitory characteristics of TRB may arise from the inhibitor being noncovalently trapped within a unique active-site gorge structure of the enzyme. It was predicted that an optimal TRB⅐AChE binding would position a narrowing connection of the TRB structure at a constricted area near the entrance of the gorge, thereby providing a structural basis for the observed irreversible binding.

MTDLs Design on AChE (Acetylcholinesterase) and β-Secretase (BACE-1): 3D-QSAR and Molecular Docking Studies

“…reason that F5 molecule is the planar conformation leading to the F5 would be advantageous to prevent ACh (acetylcholine) molecule into the gorge of AchE. The result is agreement with Chen and Ling's [36,37] result, which the plane conformation of territrem B is the ensure of high inhibitory activity. Fig.…”

In vitro inhibitory effect of aflatoxin B1 on acetylcholinesterase activity in mouse brain

“…Hence, their inhibitory mechanisms differ: whereas DFP phosphorylates the catalytic serine thus directly blocking the active site, AFB 1 inactivates the enzyme probably by blocking access of the substrate to the active site. Like other coumarin inhibitors, AFB 1 presumably acts also by interacting either with the active center or with the peripheral binding sites by inducing a defective conformational change in the enzyme through non-covalent binding, or through both mechanisms (Radic et al, 1991;Simeon-Rudolf et al, 1999;Chen et al, 1999).…”

Structural Bioinformatics and QSAR Analysis Applied to the Acetylcholinesterase and Bispyridinium Aldoximes

“…This site may contribute to the trafficking, folding, solubility, and cell-surface expression. The peptide toxin fasciculin II inhibits AChE by binding over the entrance to this cavity, the fungal metabolite territrem B binds to an area near the entrance, and huperazine binds at the bottom [54][55][56]. The first cavity includes the "peripherical anionic site" Asp74 and Tyr72, these amino acids control probably the entry of OPs and aldoximes.…”