Title : Role of water in aging of human
butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging
Abstract :
- Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases
- The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes
- However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme
- In human butyrylcholinesterase ( hBChE ), aging involves the residues His438 and Glu197 that are proximal to the active-site serine ( Ser198 )
- The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion
- Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively
- In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively
- No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE
- This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX
- The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine ( His438 )
- Interestingly, this water molecule is ideally position ed to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond
- Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond