Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6.

The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C.

Structural and kinetic evidence of aging after organophosphate inhibition of human Cathepsin A.

Human Cathepsin A (CatA) is a lysosomal serine carboxypeptidase of the renin-angiotensin system (RAS) and is structurally similar to acetylcholinesterase (AChE). CatA can remove the C-terminal amino acids of endothelin I, angiotensin I, Substance P, oxytocin, and bradykinin, and can deamidate neurokinin A. Proteomic studies identified CatA and its homologue, SCPEP1, as potential targets of organophosphates (OP).

Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6.

Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) was observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures of hAChE inhibited by a racemic mixture of VX (P ) and its enantiomers were obtained.

Nanosizing a Metal-Organic Framework Enzyme Carrier for Accelerating Nerve Agent Hydrolysis.

We report the synthesis and characterization of a water-stable zirconium metal-organic framework (MOF), NU-1003, featuring the largest mesoporous aperture known for a zirconium MOF. This material has been used to immobilize the nerve agent hydrolyzing enzyme, organophosphorus acid anhydrolase (OPAA). The catalytic efficiency of immobilized OPAA in nanosized NU-1003 is significantly increased compared to that of OPAA immobilized in microsized NU-1003 and even exceeds that of the free OPAA enzyme.

Encapsulation of a Nerve Agent Detoxifying Enzyme by a Mesoporous Zirconium Metal-Organic Framework Engenders Thermal and Long-Term Stability.

Immobilized enzymes typically have greater thermal and operational stability than their soluble form. Here we report that for the first time, a nerve agent detoxifying enzyme, organophosphorus acid anhydrolase (OPAA), has been successfully encapsulated into a water-stable zirconium metal-organic framework (MOF). This MOF features a hierarchical mesoporous channel structure and exhibits a 12 wt % loading capacity of OPAA.

Identification of small-molecule inhibitors of Yersinia pestis Type III secretion system YscN ATPase.

Yersinia pestis is a gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors.