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Abrogation of Immunogenic Properties of Gliadin Peptides through Transamidation by Microbial Transglutaminase Is Acyl-Acceptor Dependent.

ABSTRACT: Wheat gluten confers superior baking quality to wheat based products but elicits a pro-inflammatory immune response in patients with celiac disease. Transamidation of gluten by microbial transglutaminase (mTG) and tissue transglutaminase (tTG) reduces the immunogenicity of gluten; however, little information is available on the minimal modification sufficient to eliminate gliadin immunogenicity nor has the effectiveness of transamidation been studied with T-cell clones from patients. Here we demonstrate that mTG can efficiently couple three different acyl-acceptor molecules, l-lysine, glycine ethyl ester, and hydroxylamine, to gliadin peptides and protein. While all three acyl-acceptor molecules were cross-linked to the same Q-residues, not all modifications were equally effective in silencing T-cell reactivity. Finally, we observed that tTG can partially reverse the mTG-catalyzed transamidation by its isopeptidase activity. These results set the stage to determine the impact of these modifications on the baking quality of gluten proteins and in vivo immunogenicity of such food products.

SUBMITTER: Zhou L

PROVIDER: S-EPMC5579586 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Abrogation of Immunogenic Properties of Gliadin Peptides through Transamidation by Microbial Transglutaminase Is Acyl-Acceptor Dependent.

Zhou Lin L Kooy-Winkelaar Yvonne M C YMC Cordfunke Robert A RA Dragan Irina I Thompson Allan A Drijfhout Jan Wouter JW van Veelen Peter A PA Chen Hongbing H Koning Frits F

Journal of agricultural and food chemistry 20170817 34

Wheat gluten confers superior baking quality to wheat based products but elicits a pro-inflammatory immune response in patients with celiac disease. Transamidation of gluten by microbial transglutaminase (mTG) and tissue transglutaminase (tTG) reduces the immunogenicity of gluten; however, little information is available on the minimal modification sufficient to eliminate gliadin immunogenicity nor has the effectiveness of transamidation been studied with T-cell clones from patients. Here we dem ...[more]

PMID: 28771001

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Project description:In order to develop new organic materials for optoelectronic applications, a fundamental understanding of the electronic properties of specific chromophore combinations must be realized. To that end, we report "model" acceptor (A)-acceptor' (A')-acceptor (A) triads in which the pendants (A') we selected are well-known components of organic optoelectronic applications. Our pendants are sandwiched between two dialkoxyphenazine (A) through an alkyne bond. The A' was systematically increased in electron-deficiency from benzothiadiazole (BTD-P) to naphthalene diimide with octyl (NDI-O-P) or ethylhexyl groups (NDI-EH-P) to perylene diimide with ethylhexyl (PTCDI-EH-P) to assess changes in the electronic properties of the resultant molecules. Characterizations were performed using both experimental and theoretical methods. From optical and cyclic voltammetry, we found that the electron deficiency of each pendant was directly correlated to the energy level of the lowest unoccupied molecular orbital (E LUMO). When examining the simple molecular orbital diagrams produced at the B3LYP/6-31G* level of theory, the LUMOs were, as expected, primarily localized on the more electron-deficient pendants. In terms of the energy level of the highest occupied molecular orbital (E HOMO), the numerical values obtained experimentally also correlated with values obtained computationally. Attempting to construct a simplified model that would explain these correlated values was not as readily apparent, given the disparate physical characteristics of these compounds. For example, BTD-P and NDI-O-P/NDI-EH-P achieved planarity when computationally optimized, but PTCDI-EH-P adapted a "buckled" geometry on the central PTCDI, consequently forcing the attached phenazines out-of-plane. The title compounds showed solvent polarity-dependent fluorescence, which is indicative of intramolecular charge transfer. In conjunction with our theoretical study, the current system can be viewed as an extension of donor-acceptor-donor systems. Thermal properties characterized by differential scanning calorimetry revealed that reversible phase transitions were only observed for BTD-P. In addition, BTD-P was found to be an efficient gelator in 1,1,1-trichloroethane and toluene. The other compounds in this study did not form gels in any of the solvents tested, which may have been a result of the alkyl groups on the pendants hampering the fibrillation process.

Project description:Coeliac disease (CD) is a common and complex disorder of the small intestine caused by intolerance to wheat gluten and related edible cereals like barley and rye. Peptides originating from incomplete gliadin digestion activate the lamina propria infiltrating T cells to release proinflammatory cytokines, which in turn cause profound tissue remodelling of the small intestinal wall. There is no cure for CD except refraining from consuming gluten-containing products.Phage from a random oligomer display library were enriched by repeated pannings against immobilised gliadin proteins. Phage from the final panning round were plated, individual plaques picked, incubated with host bacteria, amplified to a population size of 1011 to 1012 and purified. DNA was isolated from 1000 purified phage populations and the region covering the 36 bp oligonucleotide insert from which the displayed peptides were translated, was sequenced. Altogether more than 150 different peptide-encoding sequences were identified, many of which were repeatedly isolated under various experimental conditions. Amplified phage populations, each expressing a single peptide, were tested first in pools and then one by one for their ability to inhibit binding of human anti-gliadin antibodies in ELISA assays. These experiments showed that several of the different peptide-expressing phage tested inhibited the interaction between gliadin and anti-gliadin antibodies. Finally, four different peptide-encoding sequences were selected for further analysis, and the corresponding 12-mer peptides were synthesised in vitro. By ELISA assays it was demonstrated that several of the peptides inhibited the interaction between gliadin molecules and serum anti-gliadin antibodies. Moreover, ELISA competition experiments as well as dot-blot and western blot revealed that the different peptides interacted with different molecular sites of gliadin.We believe that several of the isolated and characterised gliadin-binding peptides described here could provide valuable tools for researchers in the field of CD by facilitating studies on localisation and uptake of various gliadin peptides in the small intestine. In future work, the potential of these peptides to detoxify gluten will be investigated.

Dataset Information

Abrogation of Immunogenic Properties of Gliadin Peptides through Transamidation by Microbial Transglutaminase Is Acyl-Acceptor Dependent.

Publications

Abrogation of Immunogenic Properties of Gliadin Peptides through Transamidation by Microbial Transglutaminase Is Acyl-Acceptor Dependent.

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