Abstract
Organophosphorous nerve agents (OPNA) pose an actual and major threat for both military and civilians alike, as an upsurge in their use has been observed in the recent years. Currently available treatments mitigate the effect of the nerve agents, and could be vastly improved by means of scavengers of the nerve agents. Consequently, efforts have been made over the years into investigating enzymes, also known as bioscavengers, which have the potential either to trap or hydrolyze these toxic compounds. We investigated the previously described esterase 2 from Thermogutta terrifontis (TtEst2) as a potential bioscavenger of nerve agents. As such, we assessed its potential against G-agents (tabun, sarin, and cyclosarin), VX, as well as the pesticide paraoxon. We report that TtEst2 is a good bioscavenger of paraoxon and G-agents, but is rather slow at scavenging VX. X-ray crystallography studies showed that TtEst2 forms an irreversible complex with the aforementioned agents, and allowed the identification of amino-acids, whose mutagenesis could lead to better scavenging properties for VX. In conjunction with its cheap production and purification processes, as well as a robust structural backbone, further engineering of TtEst2 could lead to a stopgap bioscavenger useful for in corpo scavenging or skin decontamination.
Highlights
Since the Tokyo subway terror attack in 1995, organophosphorus nerve agents (OPNA,Figure 1) [1] such as sarin (GB), VX, or tabun (GA), have been considered as a major risk, for soldiers in operations, and for the civilian population
These nerve agents target acetylcholinesterase (AChE, 3.1.1.7), a key enzyme situated in the inter-synaptic cleft in the neuro-muscular junction and the central nervous system (CNS) that catalyzes the hydrolysis of the neurotransmitter acetylcholine, ensuring an efficient nerve signal transmission
We focused on a bacterial esterase as a potential bioscavenger candidate
Summary
Since the Tokyo subway terror attack in 1995, organophosphorus nerve agents (OPNA,Figure 1) [1] such as sarin (GB), VX, or tabun (GA), have been considered as a major risk, for soldiers in operations, and for the civilian population. Organophosphorus compounds are represented in pesticides and still widely used around the world, causing millions of intoxications per year due to misuse and suicide attempts [2]. These nerve agents target acetylcholinesterase (AChE, 3.1.1.7), a key enzyme situated in the inter-synaptic cleft in the neuro-muscular junction and the central nervous system (CNS) that catalyzes the hydrolysis of the neurotransmitter acetylcholine, ensuring an efficient nerve signal transmission. The OPNA reaction leads to the formation of a covalent phosphyl adduct on the catalytic serine, inhibiting the enzyme activity This results in an accumulation of the neurotransmitter, and a major cholinergic crisis. This physiologically translates to SLUDGEM symptoms (salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis, and miosis) eventually leading to respiratory distress, followed by death, in the absence of intense medical care
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