Carletti_2009_Biochem.J_421_97

Reference

Title : Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun. - Carletti_2009_Biochem.J_421_97
Author(s) : Carletti E , Aurbek N , Gillon E , Loiodice M , Nicolet Y , Fontecilla-Camps JC , Masson P , Thiermann H , Nachon F , Worek F
Ref : Biochemical Journal , 421 :97 , 2009
Abstract :

hBChE [human BChE (butyrylcholinesterase)] naturally scavenges OPs (organophosphates). This bioscavenger is currently in Clinical Phase I for pretreatment of OP intoxication. Phosphylated ChEs (cholinesterases) can undergo a spontaneous time-dependent process called 'aging' during which the conjugate is dealkylated, leading to creation of an enzyme that cannot be reactivated. hBChE inhibited by phosphoramidates such as tabun displays a peculiar resistance to oxime-mediated reactivation. We investigated the basis of oxime resistance of phosphoramidyl-BChE conjugates by determining the kinetics of inhibition, reactivation (obidoxime {1,1'-(oxybis-methylene) bis[4-(hydroxyimino) methyl] pyridinium dichloride}, TMB-4(Trimedoxime) [1,3-trimethylene-bis(4-hydroxyiminomethylpyridinium) dibromide], HL 7 {1-[[[4-(aminocarbonyl) pyridinio]methoxy]methyl]-2,4-bis-[(hydroxyimino)methyl] pyridinium dimethanesulfonate)}, HI-6 {1-[[[4-(aminocarbonyl) pyridinio] methoxy] methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride monohydrate} and aging, and the crystal structures of hBChE inhibited by different N-monoalkyl and N,N-dialkyl tabun analogues. The refined structures of aged hBChE conjugates show that aging proceeds through O-dealkylation of the P(R) enantiomer of N,N-diethyl and N-propyl analogues, with subsequent formation of a salt bridge preventing reactivation, similarly to a previous observation made on tabun-ChE conjugates. Interestingly, the N-methyl analogue projects its amino group towards the choline-binding pocket, so that aging proceeds through deamination. This orientation results from a preference of hBChE's acyl-binding pocket for larger than 2-atoms linear substituents. The correlation between the inhibitory potency and the N-monoalkyl chain length is related to increasingly optimized interactions with the acyl-binding pocket as shown by the X-ray structures. These kinetics and X-ray data lead to a structure-activity relationship that highlights steric and electronic effects of the amino substituent of phosphoramidate. This study provides the structural basis to design new oximes capable of reactivating phosphoramidyl-hBChE conjugates after intoxication, notably when hBChE is used as pretreatment, or to design BChE-based catalytic bioscavengers.

PubMedSearch : Carletti_2009_Biochem.J_421_97
PubMedID: 19368529
Gene_locus related to this paper: human-BCHE

Related information

Gene_locus human-BCHE
Structure human-BCHE    2WID    2WIF    2WIG    2WIJ    2WIK    2WIL    2WSL

Citations formats

Carletti E, Aurbek N, Gillon E, Loiodice M, Nicolet Y, Fontecilla-Camps JC, Masson P, Thiermann H, Nachon F, Worek F (2009)
Structure-activity analysis of aging and reactivation of human butyrylcholinesterase inhibited by analogues of tabun.
Biochemical Journal 421 :97

Carletti E, Aurbek N, Gillon E, Loiodice M, Nicolet Y, Fontecilla-Camps JC, Masson P, Thiermann H, Nachon F, Worek F (2009)
Biochemical Journal 421 :97