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 language | English (US) |
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Pages (from-to) | 27-41 |
Number of pages | 15 |
Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
Volume | 1537 |
Issue number | 1 |
DOIs | |
State | Published - Jul 27 2001 |
Externally published | Yes |
Keywords
- Cholera toxin
- Imidazole
- L-Histidine
- Prostaglandin
- Structure
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology