Cholera toxin-induced PGE2 activity is reduced by chemical reaction with L-histidine

Johnny W. Peterson, David King, Edward L. Ezell, Mark Rogers, Deborah Gessell, Jennifer Hoffpauer, Luis Reuss, Ashok K. Chopra, David Gorenstein

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Mediators of cholera toxin (CT)-induced fluid secretion include 3′,5′-adenosine monophosphate (cAMP), prostaglandin E2 (PGE2), and 5-hydroxytryptamine (5-HT). Administration of L-histidine significantly reduced the net secretory response of the small intestine of mice challenged with CT and reduced the capacity of PGE2 to stimulate Na+ transport in Ussing chambers. We demonstrated that L-histidine chemically modified the structure of PGE2 but had no direct effect on cAMP or 5-HT. L-Histidine and imidazole reacted with PGE2 in vitro in cell-free mixtures incubated at 37°C and pH 7.0 under an atmosphere of N2 with the formation of PGE2-imidazole and PGE2-histidine covalent adducts. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analysis of the purified adduct showed that imidazole catalyzed the dehydration of PGE2. A Michael adduct then was formed between C11 of 11-deoxy-Δ10 PGE2 (PGA2) and the tau nitrogen in the imidazole ring of L-histidine. Importantly, the isolated PGE2-imidazole and PGE2-histidine adducts inhibited CT-induced fluid loss and cAMP accumulation in mouse intestinal loops. The protection provided by PGE2-imidazole, PGE2-histidine, and L-histidine against intestinal fluid loss could provide a basis for future therapy against cholera.

Original languageEnglish (US)
Pages (from-to)27-41
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1537
Issue number1
DOIs
StatePublished - Jul 27 2001

Keywords

  • Cholera toxin
  • Imidazole
  • L-Histidine
  • Prostaglandin
  • Structure

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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    Peterson, J. W., King, D., Ezell, E. L., Rogers, M., Gessell, D., Hoffpauer, J., Reuss, L., Chopra, A. K., & Gorenstein, D. (2001). Cholera toxin-induced PGE2 activity is reduced by chemical reaction with L-histidine. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1537(1), 27-41. https://doi.org/10.1016/S0925-4439(01)00052-7