There exists a substance called TMTFA, or 3-(N,N,N-Trimethylammonio)-2,2,2-trifluoroacetophenone. It is known for being able to inhibit acetylcholinesterase at femtomolar concentrations. The TMTFA-AChE adduct resembles the tetrahedral transition state through which the hydrolysis of acetylcholine by the enzyme normally proceeds, and this adduct is stabilized by the electron-withdrawing trifluoromethyl group present in the TMTFA molecule. This inhibition is reversible.
While there have been studies regarding trifluoroacetophenones and their interactions with AChE, I haven't been able to find studies exploring the interactions between AChE and trifluoroacetates, such as 3-(N,N,N-trimethylammonio)phenyl trifluoroacetate or 2,2,2-trifluoroacetylcholine. Would these, and other, esters of trifluoroacetic acid inhibit AChE or be hydrolyzed normally? If it's the former, then what are the typical inhibitory concentrations of such esters? What is the shape of the adduct of the ester with AChE? How long would they remain bound to the enzyme? Have any studies been done regarding the bioactivity of such esters?
- Nair, H. K.; Seravalli, J.; Arbuckle, T.; Quinn, D. M. Molecular Recognition in Acetylcholinesterase Catalysis: Free-Energy Correlations for Substrate Turnover and Inhibition by Trifluoro Ketone Transition-State Analogs. Biochemistry 1994, 33(28), 8566–8576. DOI: 10.1021/bi00194a023.
- Harel, M.; Quinn, D. M.; Nair, H. K.; Silman, I.; Sussman, J. L. The X-Ray Structure of a Transition State Analog Complex Reveals the Molecular Origins of the Catalytic Power and Substrate Specificity of Acetylcholinesterase. J. Am. Chem. Soc. 1996, 118(10), 2340–2346. DOI: 10.1021/ja952232h.