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Refolded Recombinant Human Paraoxonase 1 Variant Exhibits Prophylactic Activity Against Organophosphate Poisoning

Priyanka Bajaj1, Rajan K Tripathy1, Geetika Aggarwal1

  • 1Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar (Mohali), 160062, Punjab, India.

Applied Biochemistry and Biotechnology
|May 2, 2016
PubMed

Insights

Developing effective treatments for organophosphate (OP) poisoning is crucial. A new recombinant human paraoxonase 1 (rh-PON1) variant shows enhanced OP-hydrolyzing activity and prophylactic effects in mice.

Area of Science:

  • Biochemistry
  • Toxicology
  • Enzyme Engineering

Background:

  • Organophosphate (OP) compounds are neurotoxic agents with inadequate current treatments.
  • Human paraoxonase 1 (h-PON1) can hydrolyze OP compounds, making it a potential therapeutic agent.
  • Challenges exist in producing recombinant h-PON1 (rh-PON1) for improved variants and efficacy studies.

Purpose of the Study:

  • To develop an effective Escherichia coli expression system for producing active rh-PON1.
  • To characterize the OP-hydrolyzing properties of refolded wild-type rh-PON1 and a novel variant.
  • To evaluate the in vitro, ex vivo, and in vivo efficacy of the rh-PON1 variant against OP-poisoning.

Main Methods:

  • Utilized an Escherichia coli expression system for rh-PON1 production.
  • Refolded and characterized wild-type rh-PON1 and the rh-PON1(H115W;R192K) variant.
  • Assessed OP-hydrolyzing activity in vitro and ex vivo, and prophylactic activity in a mouse model.

Main Results:

  • Successfully produced active, refolded rh-PON1 using an E. coli system.
  • The rh-PON1(H115W;R192K) variant demonstrated significantly enhanced OP-hydrolyzing activity.
  • The variant exhibited prophylactic efficacy in a mouse model of OP-poisoning.

Conclusions:

  • Refolded rh-PON1 produced via E. coli is a viable approach for enzyme production.
  • The engineered rh-PON1(H115W;R192K) variant shows promise as a therapeutic candidate for OP-poisoning.
  • Further development of refolded rh-PON1 could lead to improved treatments for OP intoxication.
Keywords:
AcetylcholinesteraseChlorpyrifosoxonOrganophosphateParaoxonase 1Prophylactic

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