Title : Structural evidence that human
acetylcholinesterase inhibited by tabun ages through O-dealkylation
Abstract :
- Tabun is a warfare agent that inhibits human acetylcholinesterase ( hAChE ) by rapid phosphylation of the catalytic serine
- A time-dependent reaction occurs on the tabun adduct, leading to an "aged" enzyme , resistant to oxime reactivators
- The aging reaction may proceed via either dealkylation or deamidation, depending on the stereochemistry of the phosphoramidyl adduct
- We solved the X-ray structure of aged tabun- hAChE complexed with fasciculin II, and we show that aging proceeds through O-dealkylation, in agreement with the aging mechanism that we determined for tabun-inhibited human butyrylcholinesterase and mouse acetylcholinesterase
- Noteworthy, aging and binding of fasciculin II lead to an improved thermostability, resulting from additional stabilizing interactions between the two subdomains that face each other across the active site gorge
- This first structure of hAChE inhibited by a nerve agent provides structural insight into the inhibition and aging mechanisms and a structural template for the design of molecules capable of reactivating aged hAChE