Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Molecules. 2017 Sep 4;22(9):1464. doi: 10.3390/molecules22091464.
Organophosphorus agents are potent inhibitors of acetylcholinesterase. Inhibition involves successive chemical events. The first is phosphylation of the active site serine to produce a neutral adduct, which is a close structural analog of the acylation transition state. This adduct is unreactive toward spontaneous hydrolysis, but in many cases can be reactivated by nucleophilic medicinal agents, such as oximes. However, the initial phosphylation reaction may be followed by a dealkylation reaction of the incipient adduct. This reaction is called aging and produces an anionic phosphyl adduct with acetylcholinesterase that is refractory to reactivation. This review considers why the anionic aged adduct is unreactive toward nucleophiles. An alternate approach is to realkylate the aged adduct, which would render the adduct reactivatable with oxime nucleophiles. However, this approach confronts a considerable-and perhaps intractable-challenge: the aged adduct is a close analog of the deacylation transition state. Consequently, the evolutionary mechanisms that have led to transition state stabilization in acetylcholinesterase catalysis are discussed herein, as are the challenges that they present to reactivation of aged acetylcholinesterase.
有机磷化合物是乙酰胆碱酯酶的强效抑制剂。抑制作用涉及连续的化学事件。第一步是磷酰化活性丝氨酸，产生中性加合物，它是酰化过渡态的紧密结构类似物。该加合物对自发水解没有反应性，但在许多情况下可以被亲核药物如肟重新激活。然而，初始的磷酰化反应可能会被起始加合物的脱烷基反应所跟随。这种反应称为老化，产生带负电荷的磷酰基与乙酰胆碱酯酶的加合物，该加合物对重新激活具有抗性。本文考虑了为什么带负电荷的老化加合物对亲核试剂没有反应性。另一种方法是重新烷基化老化的加合物，这将使加合物能够与肟亲核试剂重新反应。然而，这种方法面临着相当大的——也许是难以解决的——挑战：老化的加合物是去酰化过渡态的紧密类似物。因此，本文讨论了导致乙酰胆碱酯酶催化中过渡态稳定的进化机制，以及它们对老化乙酰胆碱酯酶重新激活带来的挑战。
