Intestinal digestive resistance of immunodominant gliadin peptides

Hausch, Felix; Shan, Lu; Santiago, Nilda A.; Gray, Gary M.; Khosla, Chaitan

doi:10.1152/ajpgi.00136.2002

Cited by 326 publications

(261 citation statements)

References 27 publications

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“…1 Most T-cell epitopes harbor glutamate residues that have been deamidated from glutamine residues by the action of tissue transglutaminase (11,12). Proline residues confer resistance to proteolysis by digestive enzymes (13) and influence the selective targeting of glutamine residues by tissue transglutaminase (14,15).…”

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confidence: 99%

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Bergseng

Xia²,

Kim³

et al. 2005

Journal of Biological Chemistry

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Binding of peptide epitopes to major histocompatibility complex proteins involves multiple hydrogen bond interactions between the peptide main chain and major histocompatibility complex residues. The crystal structure of HLA-DQ2 complexed with the ␣I-gliadin epitope (LQPFPQPELPY) revealed four hydrogen bonds between DQ2 and peptide main chain amides. This is remarkable, given that four of the nine core residues in this peptide are proline residues that cannot engage in amide hydrogen bonding. Preserving main chain hydrogen bond interactions despite the presence of multiple proline residues in gluten peptides is a key element for the HLA-DQ2 association of celiac disease. We have investigated the relative contribution of each main chain hydrogen bond interaction by preparing a series of Nmethylated ␣I epitope analogues and measuring their binding affinity and off-rate constants to DQ2. Additionally, we measured the binding of ␣I-gliadin peptide analogues in which norvaline, which contains a backbone amide hydrogen bond donor, was substituted for each proline. Our results demonstrate that hydrogen bonds at P4 and P2 positions are most important for binding, whereas the hydrogen bonds at P9 and P6 make smaller contributions to the overall binding affinity. There is no evidence for a hydrogen bond between DQ2 and the P1 amide nitrogen in peptides without proline at this position. This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease.

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Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Bergseng

Xia²,

Kim³

et al. 2005

Journal of Biological Chemistry

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“…Digestion is pursued in the small intestine (pH 5-7) by pancreatic proteases (e.g., trypsin and chymotrypsin) and brush-border membrane enzymes, leading to amino acids and oligopeptides which are then absorbed (8,9). Owing to their exceptionally high proline and glutamine content, immunogenic peptides from gluten resist enzymatic degradation by GI enzymes (10).…”

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confidence: 99%

In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract

Fuhrmann

Leroux

2011

Proc. Natl. Acad. Sci. U.S.A.

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Exogenous enzymes are administered orally to treat several diseases, such as pancreatic insufficiency and lactose intolerance. Due to the proteinaceous nature of enzymes, they are subject to inactivation and/or digestion in the gastrointestinal (GI) tract. Here we describe a convenient fluorescence-based assay to monitor the activity of therapeutic enzymes in real time in vivo in the GI tract. To establish the proof of principle, the assay was applied to proline-specific endopeptidases (PEPs), a group of enzymes recently proposed as adjuvant therapy for celiac disease (a highly prevalent immunogenetic enteropathy). A short PEP-specific peptide sequence which is part of larger immunotoxic sequences of gluten was labeled with a fluorescent dye and a corresponding quencher. Upon enzymatic cleavage, the fluorescence emission was dequenched and detected with an in vivo imaging system. PEPs originating from Flavobacterium meningosepticum (FM) and Myxococcus xanthus (MX) were evaluated after oral administration in rats. While MX PEP could not cleave the peptide in the stomach, FM PEP showed significant gastric activity reaching 40–60% of the maximal in vivo signal intensity. However, both enzymes produced comparable fluorescence signals in the small intestine. Coadministration of an antacid drug significantly enhanced MX PEP’s gastric activity due to increased pH and/or inhibition of stomach proteases. With this simple procedure, differences in the in vivo performance of PEPs, which could not be identified under in vitro conditions, were detected. This imaging assay could be used to study other oral enzymes in vivo and therefore be instrumental in improving their therapeutic efficiency.

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“…Hausch et al (2002) comment on immunodominant epitopes that are considered difficult to digest because of the low activity of enzymes capable of N-terminal and C-terminal attack on proline residues (DPPIV and pancreatic endoproteases respectively). These epitopes are probably more important from the point of view of their particular key amino acid sequences, particularly ones that contain tyrosine, rather than their high proline content.…”

Section: A Unified Theory Of CDmentioning

confidence: 99%