A computer modeling study for the inhibition mechanism of Territrem B on acetylcholinesterase

• Main Authors: Luo, Ying-Ling, 羅英玲
• Other Authors: Fu-Chuo Peng
• Format: Others
• Language: zh-TW
• Published: 1998
• Online Access: http://ndltd.ncl.edu.tw/handle/74882755662171146769

碩士 === 國立臺灣大學 === 毒理學研究所 === 86 === Abstract Territrem B (TRB), a tremorgenic mycotoxin isolated from rice cultures of Aspergillus terreus 23-1, is a potent, irreversible and noncovalent inhibitor of eel acetylcholinesterase(AChE, EC 3.1.1.7) Here a computer docking simulation study was carried out with the aim to understand the inhibition mechanism of TRB on AChE. The docking results indicated that both the aromatic head or the non-aromatic tail moiety of TRB inserted into the a ctive gorge of AChE. However, from a combination of analysis on both structural and biochemical data, a low-energy model, T2 , latter the former configuration,appears to be most consistent with the experimental evidence. Interestingly, in the T2 model, no contacts between TRB and the catalytic residues of AChE were found, and TRB, by insection, blocked the access to the gorge, while inducing conformational change of several aromatic residues of the gorge structure and contraction of the gorge gate. This simulation result is in agreement with kinetic data, indicating that hydrolysis of the substrate acetylcholine by AChE could be hindered by an irreversible TRB blocking in the gorge. The potent inhibition of AChE by a very low concentration of TRB could also be attributed to favorable hydrophobic and hydrogen-bonded interactions between TRB and AChE. These favorable interactions include the hydrophobic face of TRB interacting with Trp84, Trp279, and Phe334, and the hydrophilic face of TRB hydrogen bonding with Tyr70,Tyr121.