Height JJ

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Full name : Height Jude J

First name : Jude J

Mail : Edgewood Chemical Biological Center, Aberdeen Proving Ground, Maryland 21010

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References (6)

Title : Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6 - McGuire_2021_Chem.Res.Toxicol_34_804
Author(s) : McGuire JR , Bester SM , Guelta MA , Cheung J , Langley C , Winemiller MD , Bae SY , Funk V , Myslinski JM , Pegan SD , Height JJ
Ref : Chemical Research in Toxicology , 34 :804 , 2021
Abstract : 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. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.
ESTHER : McGuire_2021_Chem.Res.Toxicol_34_804
PubMedSearch : McGuire_2021_Chem.Res.Toxicol_34_804
PubMedID: 33538594
Gene_locus related to this paper: human-ACHE

Title : The structural and biochemical impacts of monomerizing human acetylcholinesterase - Bester_2019_Protein.Sci_28_1106
Author(s) : Bester SM , Adipietro KA , Funk VL , Myslinski JM , Keul ND , Cheung J , Wilder PT , Wood ZA , Weber DJ , Height JJ , Pegan SD
Ref : Protein Science , 28 :1106 , 2019
Abstract : Serving a critical role in neurotransmission, human acetylcholinesterase (hAChE) is the target of organophosphate nerve agents. Hence, there is an active interest in studying the mechanism of inhibition and recovery of enzymatic activity, which could lead to better countermeasures against nerve agents. As hAChE is found in different oligomeric assemblies, certain approaches to studying it have been problematic. Herein, we examine the biochemical and structural impact of monomerizing hAChE by using two mutations: L380R/F535K. The activities of monomeric hAChE L380R/F535K and dimeric hAChE were determined to be comparable utilizing a modified Ellman's assay. To investigate the influence of subunit-subunit interactions on the structure of hAChE, a 2.1 A X-ray crystallographic structure was determined. Apart from minor shifts along the dimer interface, the overall structure of the hAChE L380R/F535K mutant is similar to that of dimeric hAChE. To probe whether the plasticity of the active site was overtly impacted by monomerizing hAChE, the kinetic constants of (PR/S ) - VX (ethyl({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate) inhibition and subsequent rescue of hAChE L380R/F535K activity with HI-6 (1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4'-carbamoyl-1-pyridinium)) were determined and found to be comparable to those of dimeric hAChE. Thus, hAChE L380R/F535K could be used as a substitute for dimeric hAChE when experimentally probing the ability of the hAChE active site to accommodate future nerve agent threats or judge the ability of new therapeutics to access the active site.
ESTHER : Bester_2019_Protein.Sci_28_1106
PubMedSearch : Bester_2019_Protein.Sci_28_1106
PubMedID: 30993792
Gene_locus related to this paper: human-ACHE

Title : Synthesis and Molecular Properties of Nerve Agent Reactivator HLo-7 Dimethanesulfonate - Hsu_2019_ACS.Med.Chem.Lett_10_761
Author(s) : Hsu FL , Bae SY , McGuire J , Anderson DR , Bester SM , Height JJ , Pegan SD , Walz AJ
Ref : ACS Med Chem Lett , 10 :761 , 2019
Abstract : The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HLo-7 is a potential second-generation therapeutic reactivator. A synthetic process for HLo-7 is detailed with improvements to the DIBAL reduction and ion exchange steps. HLo-7 was visualized for the first time within the active site of human acetylcholinesterase and its relative ex vivo potency confirmed against various nerve agents using a phrenic nerve hemidiaphragm assay.
ESTHER : Hsu_2019_ACS.Med.Chem.Lett_10_761
PubMedSearch : Hsu_2019_ACS.Med.Chem.Lett_10_761
PubMedID: 31097996
Gene_locus related to this paper: human-ACHE

Title : An OPAA enzyme mutant with increased catalytic efficiency on the nerve agents sarin, soman, and GP - Bae_2018_Enzyme.Microb.Technol_112_65
Author(s) : Bae SY , Myslinski JM , McMahon LR , Height JJ , Bigley AN , Raushel FM , Harvey SP
Ref : Enzyme Microb Technol , 112 :65 , 2018
Abstract : The wild-type OPAA enzyme has relatively high levels of catalytic activity against several organophosphate G-type nerve agents. A series of mutants containing replacement amino acids at the OPAA Y212, V342, and I215 sites showed several fold enhanced catalytic efficiency on sarin, soman, and GP. One mutant, Y212F/V342L, showed enhanced stereospecificity on sarin and that enzyme along with a phosphotriesterase mutant, GWT, which had the opposite stereospecificity, were used to generate enriched preparations of each sarin enantiomer. Inhibition of acetylcholinesterase by the respective enantioenriched sarin solutions subsequently provided identification of the sarin enantiomers as separated by normal phase enantioselective liquid chromatography coupled with atmospheric pressure chemical ionization-mass spectrometry.
ESTHER : Bae_2018_Enzyme.Microb.Technol_112_65
PubMedSearch : Bae_2018_Enzyme.Microb.Technol_112_65
PubMedID: 29499783

Title : Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6 - Bester_2018_Chem.Res.Toxicol_31_1405
Author(s) : Bester SM , Guelta MA , Cheung J , Winemiller MD , Bae SY , Myslinski J , Pegan SD , Height JJ
Ref : Chemical Research in Toxicology , 31 :1405 , 2018
Abstract : 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 R/S) and its enantiomers were obtained. Beyond identifying hAChE structural features that lend themselves to stereospecific inhibition, structures of the reactivator HI-6 bound to hAChE inhibited by VX enantiomers of varying toxicity, or in its uninhibited state, were obtained. Comparison of hAChE in these pre-reactivation and post-reactivation states along with enzymatic data reveals the potential influence of unproductive reactivator poses on the efficacy of these types of therapeutics. The recognition of structural features related to hAChE's stereospecificity toward VX shed light on the molecular influences of toxicity and their effect on reactivators. In addition to providing a better understanding of the innate issues with current reactivators, an avenue for improvement of reactivators is envisioned.
ESTHER : Bester_2018_Chem.Res.Toxicol_31_1405
PubMedSearch : Bester_2018_Chem.Res.Toxicol_31_1405
PubMedID: 30462502
Gene_locus related to this paper: human-ACHE

Title : Structures of human acetylcholinesterase in complex with pharmacologically important ligands - Cheung_2012_J.Med.Chem_55_10282
Author(s) : Cheung J , Rudolph MJ , Burshteyn F , Cassidy MS , Gary EN , Love J , Franklin MC , Height JJ
Ref : Journal of Medicinal Chemistry , 55 :10282 , 2012
Abstract : Human acetylcholinesterase (AChE) is a significant target for therapeutic drugs. Here we present high resolution crystal structures of human AChE, alone and in complexes with drug ligands; donepezil, an Alzheimer's disease drug, binds differently to human AChE than it does to Torpedo AChE. These crystals of human AChE provide a more accurate platform for further drug development than previously available.
ESTHER : Cheung_2012_J.Med.Chem_55_10282
PubMedSearch : Cheung_2012_J.Med.Chem_55_10282
PubMedID: 23035744
Gene_locus related to this paper: human-ACHE