Samanta_2009_Biochem.Pharmacol_78_420

Reference

Title : Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes - Samanta_2009_Biochem.Pharmacol_78_420
Author(s) : Samanta U , Kirby SD , Srinivasan P , Cerasoli DM , Bahnson BJ
Ref : Biochemical Pharmacology , 78 :420 , 2009
Abstract :

The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(R) stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

PubMedSearch : Samanta_2009_Biochem.Pharmacol_78_420
PubMedID: 19394314
Gene_locus related to this paper: human-PLA2G7

Related information

Inhibitor Sarin
Gene_locus human-PLA2G7
Structure 3F96    3F97    3F98    3F9C

Citations formats

Samanta U, Kirby SD, Srinivasan P, Cerasoli DM, Bahnson BJ (2009)
Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes
Biochemical Pharmacology 78 :420

Samanta U, Kirby SD, Srinivasan P, Cerasoli DM, Bahnson BJ (2009)
Biochemical Pharmacology 78 :420