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J Biol Chem, Vol. 274, Issue 49, 34916-34923, December 3, 1999

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

Jen-Wei Chen, Ying-Ling Luo^§¶, Ming-Jing Hwang^¶, Fu-Chuo Peng^§, and Kuo-Huang Ling

From the  Institute of Biochemistry and ^§ Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100 Taiwan and ^¶ Division of Structural Biology, Institute of Biomedical Sciences, Academia Sinica, Taipei, 115 Taiwan

Territrem B (TRB) is a fungal metabolite isolated from Aspergillus 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 nM¹ min¹. 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 TRB·AChE 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.

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