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Event: 2262

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Neuropathy target esterase, inhibited

Short name

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NTE, inhibited

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

Organ term
nervous system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
	neuropathy target esterase	decreased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Inhibition of NTE leading to delayed neuropathy via LPS cell membrane integration	MolecularInitiatingEvent	Brooke Bowe (send email)	Under development: Not open for comment. Do not cite
Inhibition of NTE leading to delayed neuropathy via increased inflammation	MolecularInitiatingEvent	Brooke Bowe (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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Sex Applicability

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Term	Evidence
Unspecific

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

This is an integral membrane protein found in both neural and non-neural tissues that has been highly conserved throughout evolution (van Tienhoven, Atkins, Li, & Glynn, 2002). Although the exact physiologic function of NTE is still not fully understood, this serine hydrolase appears to preferentially hydrolyze phospholipids and has been deduced to be a lysophospholipase (Wijeyesakere & Richardson, 2010; Quistad, Barlow, Winrow, Sparks, & Casida, 2003). It’s function in nervous tissue is believed to be involved in axonal maintenance and membrane lipid homeostasis and thus its disruption can lead to negative downstream neurological effects (Eskut & Koskderelioglu, 2021; Read, Li, Chao, Cavanagh, & Glynn, 2009; Richardson, et al., 2020).

Figure 2: Two-step reaction of NTE inhibition and aging. In the upper reaction, binding of the chemical inhibits the enzyme via phosphorylation followed by an irreversible aging reaction that displaces an R group attached to oxygen (pathway of the “neurotoxic” organophosphates). In the lower reaction, the enzyme is inhibited but aging does not occur due to stability of the phosphorous-carbon bonds of the attached compound on the NTE (pathway of the “non-neurotoxic” organophosphates, carbamates, and sulphonates). Image adapted from: (Richardson, et al., 2020).

Discovery of this enzyme was a direct product of the investigation on how organophosphates can lead to delayed neuropathy (Johnson, 1970). Preliminary studies looking at why only some organophosphates and related compounds cause OPIDN while others are unable to give rise to delayed neuropathy found that inhibition of the novel NTE enzyme occurs through a two-step process (figure 2). First, organophosphates and structurally similar chemicals are able to interact with the serine esterase domain of NTE via phosphorylation, greatly slowing down its rate of hydrolysis and making it essentially inhibited. The second step is an irreversible “aging” reaction in which the organophosphate loses an R group on an ester or amide bond, leaving behind a negatively charged phosphonyl group attached to the NTE which completes the inhibition (Johnson, 1974; Clothier & Johnson, 1979; Wijeyesakere & Richardson, 2010).

How It Is Measured or Detected

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Domain of Applicability

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References

List of the literature that was cited for this KE description. More help

Clothier, B., & Johnson, M. K. (1979). Rapid Aging of Neurotoxic Esterase after Inhibition by Di-isopropyl Phosphorofluoridate. Biochemical Journal, 177(2), 549-558.

Eskut, N., & Koskderelioglu, A. (2021). Neurotoxic Agents and Peripheral Neuropathy. In S. Sabuncuoglu, Neurotoxicity - New Advances. IntechOpen.

Johnson, M. K. (1970). Organophosphorus and other inhibitors of brain 'neurotoxic esterase' and the development of delayed neurotoxicity in hens. Biochemical Journal, 120(3), 523–531.

Johnson, M. K. (1974). The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphorus esters. Journal of Neurochemistry, 23(4), 785–789.

Quistad, G. B., Barlow, C., Winrow, C. J., Sparks, S. E., & Casida, J. E. (2003). Evidence that mouse brain neuropathy target esterase is a lysophospholipase. Proceedings of the National Academy of Sciences, 100(13), 7983-7987.

Read, D. J., Li, Y., Chao, M. V., Cavanagh, J. B., & Glynn, P. (2009). Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance. The Journal of Neuroscience, 29(37), 11594 –11600.

Richardson, R. J., Fink, J. K., Glynn, P., Hufnagel, R. B., Makhaeva, G. F., & Wijeyesakere, S. J. (2020). Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN). In M. Aschner, & L. G. Costa, Advances in Neurotoxicology (Vol. 4, pp. 1-78). Academic Press.

van Tienhoven, M., Atkins, J., Li, Y., & Glynn, P. (2002). Human Neuropathy Target Esterase Catalyzes Hydrolysis of Membrane Lipids. Journal of Biological Chemistry, 277(23), 20942-20948.

Wijeyesakere, S. J., & Richardson, R. J. (2010). Neuropathy Target Esterase. In R. Krieger, Hayes' Handbook of Pesticide Toxicology (pp. 1435-1455). Academic Press.