Newly observed spontaneous activation of ethephon as a butyrylcholinesterase inhibitor

Mariya S. Liyasova, Lawrence M Schopfer, Sean Kodani, Stephen R. Lantz, John E. Casida, Oksana Lockridge

Research output: Contribution to journalArticle

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Abstract

The plant growth regulator ethephon (2-chloroethylphosphonic acid) inhibits human butyrylcholinesterase (BChE) by making a covalent adduct on the active site serine 198. Our goal was to extend earlier studies on ethephon inhibition. Addition of freshly prepared ethephon to BChE in buffered medium, at pH 7.0 and 22 C, resulted in no inhibition initially. However, inhibition developed progressively over 60 min of incubation. Preincubation of ethephon in pH 7-9 buffers increased its initial inhibitory potency. These observations indicated that ethephon itself was not the inhibitor. About 3% of the initial ethephon could be trapped as a BChE adduct. Mass spectral analysis of the active site peptide from inhibited BChE showed that the inhibitor added a mass of 108 Da to the active site serine on peptide FGES198AGAAS. This result rules out a previous hypothesis that ethephon adds HPO3 to BChE (added mass of 80 Da). To accommodate these observations, we propose that in aqueous media at neutral to slightly alkaline pH about 3% of the ethephon is converted (t 1/2 = 9.9 h at pH 7.0) into a cyclic oxaphosphetane which is the actual BChE inhibitor forming the 2-hydroxyethylphosphonate adduct on BChE at Ser198 while about 97% of the ethephon breaks down to ethylene (t1/2 = 11-48 h at pH 7.0) which is responsible for plant growth regulation.

Original languageEnglish (US)
Pages (from-to)422-431
Number of pages10
JournalChemical Research in Toxicology
Volume26
Issue number3
DOIs
StatePublished - Mar 18 2013

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Butyrylcholinesterase
Chemical activation
Catalytic Domain
Serine
ethephon
Peptides
Plant Growth Regulators
Spectrum analysis
Buffers

ASJC Scopus subject areas

  • Toxicology

Cite this

Newly observed spontaneous activation of ethephon as a butyrylcholinesterase inhibitor. / Liyasova, Mariya S.; Schopfer, Lawrence M; Kodani, Sean; Lantz, Stephen R.; Casida, John E.; Lockridge, Oksana.

In: Chemical Research in Toxicology, Vol. 26, No. 3, 18.03.2013, p. 422-431.

Research output: Contribution to journalArticle

Liyasova, Mariya S. ; Schopfer, Lawrence M ; Kodani, Sean ; Lantz, Stephen R. ; Casida, John E. ; Lockridge, Oksana. / Newly observed spontaneous activation of ethephon as a butyrylcholinesterase inhibitor. In: Chemical Research in Toxicology. 2013 ; Vol. 26, No. 3. pp. 422-431.
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abstract = "The plant growth regulator ethephon (2-chloroethylphosphonic acid) inhibits human butyrylcholinesterase (BChE) by making a covalent adduct on the active site serine 198. Our goal was to extend earlier studies on ethephon inhibition. Addition of freshly prepared ethephon to BChE in buffered medium, at pH 7.0 and 22 C, resulted in no inhibition initially. However, inhibition developed progressively over 60 min of incubation. Preincubation of ethephon in pH 7-9 buffers increased its initial inhibitory potency. These observations indicated that ethephon itself was not the inhibitor. About 3{\%} of the initial ethephon could be trapped as a BChE adduct. Mass spectral analysis of the active site peptide from inhibited BChE showed that the inhibitor added a mass of 108 Da to the active site serine on peptide FGES198AGAAS. This result rules out a previous hypothesis that ethephon adds HPO3 to BChE (added mass of 80 Da). To accommodate these observations, we propose that in aqueous media at neutral to slightly alkaline pH about 3{\%} of the ethephon is converted (t 1/2 = 9.9 h at pH 7.0) into a cyclic oxaphosphetane which is the actual BChE inhibitor forming the 2-hydroxyethylphosphonate adduct on BChE at Ser198 while about 97{\%} of the ethephon breaks down to ethylene (t1/2 = 11-48 h at pH 7.0) which is responsible for plant growth regulation.",
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