Barak_2000_Biochemistry_39_1156

Reference

Title : Evidence for P-N bond scission in phosphoroamidate nerve agent adducts of human acetylcholinesterase - Barak_2000_Biochemistry_39_1156
Author(s) : Barak D , Ordentlich A , Kaplan D , Barak R , Mizrahi D , Kronman C , Segall Y , Velan B , Shafferman A
Ref : Biochemistry , 39 :1156 , 2000
Abstract :

Acetylcholinesterases (AChEs) form conjugates with certain highly toxic organophosphorus (OP) agents that become gradually resistant to reactivation. This phenomenon termed "aging" is a major factor limiting the effectiveness of therapy in certain cases of OP poisoning. While AChE adducts with phosphonates and phosphates are known to age through scission of the alkoxy C-O bond, the aging path for adducts with phosphoroamidates (P-N agents) like the nerve agent N,N-dimethylphosphonocyanoamidate (tabun) is not clear. Here we report that conjugates of tabun and of its butyl analogue (butyl-tabun) with the E202Q and F338A human AChEs (HuAChEs) age at similar rates to that of the wild-type enzyme. This is in marked contrast to the large effect of these substitutions on the aging of corresponding adducts with phosphates and phosphonates, suggesting that a different aging mechanism may be involved. Both tabun and butyl-tabun appear to be similarly accommodated in the active center, as suggested by molecular modeling and by kinetic studies of phosphylation and aging with a series of HuAChE mutants (E202Q, F338A, F295A, F297A, and F295L/F297V). Mass spectrometric analysis shows that HuAChE adduct formation with tabun and butyl-tabun occurs through loss of cyanide and that during the aging process both of these adducts show a mass decrease of 28 +/- 4 Da. Due to the nature of the alkoxy substituent, such mass decrease can be unequivocally assigned to loss of the dimethylamino group, at least for the butyl-tabun conjugate. This is the first demonstration that AChE adducts with toxic P-N agents can undergo aging through scission of the P-N bond.

PubMedSearch : Barak_2000_Biochemistry_39_1156
PubMedID: 10653663

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Citations formats

Barak D, Ordentlich A, Kaplan D, Barak R, Mizrahi D, Kronman C, Segall Y, Velan B, Shafferman A (2000)
Evidence for P-N bond scission in phosphoroamidate nerve agent adducts of human acetylcholinesterase
Biochemistry 39 :1156

Barak D, Ordentlich A, Kaplan D, Barak R, Mizrahi D, Kronman C, Segall Y, Velan B, Shafferman A (2000)
Biochemistry 39 :1156