Département de Toxicologie, Institut de Recherche Biomédicale des Armées - CRSSA, La Tronche, France.
Chem Biol Interact. 2013 Mar 25;203(1):19-23. doi: 10.1016/j.cbi.2012.08.005. Epub 2012 Aug 16.
Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase.
有机磷神经毒剂不可逆地抑制乙酰胆碱酯酶。磷酰化的催化丝氨酸可以被像肟这样的强亲核试剂逆转。但是磷酰化加合物可以通过快速的自发反应生成老化的酶，即不再被肟重新激活的共轭酶。重新获得可反应性的一种策略是烷基化磷酰化加合物。合成了特定的烷基化分子，并解析了它们与人丁酰胆碱酯酶形成的复合物的晶体结构。尽管这些化合物结合在老化酶的活性部位峡谷中，但烷基化功能的取向似乎不适合于有效地烷基化磷酰化加合物。然而，这些晶体结构提供了关键信息，可用于设计有效的老化丁酰胆碱酯酶烷基化剂和丁酰胆碱酯酶的特定重激活剂。
