International Journal of Celiac Disease
ISSN (Print): 2334-3427 ISSN (Online): 2334-3486 Website: http://www.sciepub.com/journal/ijcd Editor-in-chief: Samasca Gabriel
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International Journal of Celiac Disease. 2016, 4(4), 113-120
DOI: 10.12691/ijcd-4-4-2
Open AccessReview Article

The Significance of Key Amino Acid Sequences in the Digestibility and Toxicity of Gliadin Peptides in Celiac Disease

Hugh J. Cornell1 and Teodor Stelmasiak2,

1RMIT University, School of Applied Sciences, Melbourne, Australia

2Glutagen Pty Ltd, Maribyrnong, Victoria, Australia

Pub. Date: December 03, 2016

Cite this paper:
Hugh J. Cornell and Teodor Stelmasiak. The Significance of Key Amino Acid Sequences in the Digestibility and Toxicity of Gliadin Peptides in Celiac Disease. International Journal of Celiac Disease. 2016; 4(4):113-120. doi: 10.12691/ijcd-4-4-2

Abstract

The importance of alternative or adjunct treatments to the gluten-free diet in celiac disease is now being recognized. This paper discusses the scientific principles behind the use of caricain for enzyme therapy. Objective: To review the structures of the toxic peptides in A-gliadin that relate to those found by other workers insofar as having key sequences of amino acids or motifs which relate to toxicity, especially in regard to difficulty of digestion or immunogenicity. Methods: Structures of synthetic A-gliadin peptides shown to be toxic in the fetal chick assay were examined before and after digestion with duodenal mucosa from patients in long remission. Synthetic peptides corresponding to the undigested residues were also assayed and the key amino acid sequences compared in order to determine if they could be related to direct toxicity and immunogenicity of the peptides. Results: The results showed that the smallest toxic peptides from celiac mucosal digestion were octa-peptides and that they were obtained in greater yield than similar products from normal digestion. One of those peptides corresponded to residues 12-19 of A-gliadin and contained the key motifs PSQQ and QQQP of De Ritis et al. , whilst the other corresponded to residues 72-79 and contained the key motif PYPQ (extending to PYPQPQ), observed by other workers, especially those who have been investigating immunological activity over the past two decades. Conclusions: The presence of key motifs in undigested residues from celiac mucosal digestion and the greater prevalence of these residues compared with residues from normal digestion justifies our work on enzyme therapy. These studies have also indicated that our use of caricain as an enzyme capable of digesting peptides with two different types of toxicity has a sound scientific basis.

Keywords:
celiac disease enzyme therapy gliadin peptides amino acid sequences caricain gluten

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References:

[1]  De Ritis G., Auricchio S, Jones H W, Lew E J L, Bernardin J E & Kasarda D. (1988) In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in coeliac disease. Gastroenterology. 94: 41-49.
 
[2]  Gottlieb K, Donovan J, Hussain F and Murray J A. (2015) Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials. Gastroenterology Report, 1-12 Oxford.
 
[3]  Wungiranirun M, Kelly C.P. and Leffler D A. (2016) Current status of celiac disease drug development. J Gastroenterology.
 
[4]  Ludvigsson J F, Rubio-Tapia A, van Dyke CT, et al. (2013) Increasing incidence of celiac disease in a North American population. Am J Gastroenterol. 108: 818-824.
 
[5]  Lohi S, Mustalahti K, Kaukinen K, et al. (2007) Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther. 26: 1217-25.
 
[6]  Rubio-Tapia A, Hill ID, Kelly CP, et al. (2013) ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 108: 656-76.
 
[7]  West J, Logan R F, Smith C J et al. (2004) Malignancy and mortality in people with coeliac disease: population based cohort study. BMJ. 329: 716-719.
 
[8]  Hall NJ, Rubin GP, Charnock A. (2013) Intentional and inadvertent non-adherence in adult coeliac disease. A cross-sectional survey. Appetite 68: 56-62.
 
[9]  Cornell H J, Macrae F A, Melny J, Pizzey C, Cook F, Mason S, Bhathal P & Stelmasiak T. (2005) Enzyme therapy for management of coeliac disease. Scand. J. Gastroent. 40: 1304-1312.
 
[10]  Zebrowska A, Cornell HJ, Macrae FA, Sysa-Jedrzejowska A, Waszczykowska A, Stelmasiak T. (2014) The effect of enzyme therapy on skin symptoms and immune responses in patients with dermatitis herpetiformis. International Journal of Celiac Disease. 2 (2): 58-63.
 
[11]  Cornell H J, Czyzewska A , Macrae F A, Rydzewska G, Nasierowska-Gutmejer A, Bednarczuk A and Stelmasiak T (2016) The Effect of Enzyme Supplementation on Symptoms and Duodenal Histology in Celiac Patients. International Journal of Celiac Disease. 4, No. 2, xx.
 
[12]  Kocna P, Mothes T, Krchnak V & Fric P (1991). Relationship between gliadin peptide structure and their effect on the foetal chick duodenum. Z. Lebensm. Unters. Forsch. 192: 116-119.
 
[13]  Cornell HJ, & Rivett DE (1995). In vitro mucosal digestion of synthetic gliadin-derived peptides in coeliac disease. J Protein Chem. 14: 335-339.
 
[14]  Mothes T, Muhle W, Muller F & Herkens WTJM (1985). Influence of gliadin on foetal chick intestine in tissue culture. Biol Neonate. 48: 59-64.
 
[15]  Cornell HJ, Mothes T (1993). The activity of wheat gliadin peptides in in vitro assays for coeliac disease. Biochim Biophys Acta. 1181: 169-173.
 
[16]  Cornell HJ, Mothes T (1995). Further studies of the in vitro activity of synthetic gliadin peptides in coeliac disease. Biochim Biophys Acta. 1270: 168-172.
 
[17]  Cornell HJ, Wieser H. & Belitz, HD (1992). Characterisation of the gliadin-derived peptides which are biologically active in coeliac disease. Clin Chim Acta. 213: 37-50.
 
[18]  Mantzaris, GJ, & Jewell DP (1991). In-vivo toxicity of a synthetic dodecapeptide from A-gliadin in patients with coeliac disease. Scand J Gastroenterol. 26: 392-398.
 
[19]  Giovannini C, Luchetti R and De Vincenzi M (1997) The activities of peptides “31-43” and “56-68” of A-gliadin on in vitro cultures of Ca Co-2 cells. ATLA 25:437-443.
 
[20]  Shan L., Molberg Ø, Parrot I., Hausch F, Filiz F, Gray GM, Sollid LM & Khosla C. (2002.) Structural basis for gluten intolerance in coeliac sprue. Science. 297: 2275-2279.
 
[21]  Anderson RP, Degano P, Godkin A J, Jewell D P & Hill A V S. (2000) In vivo antigen challenge in celiac disease identifies a single traqnsglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nature Medicine. 6 (3): 337-342.
 
[22]  Cornell H.J., Skerritt J.H., Puy R.& Javadpour M. (1994). Studies of in vitro γ- interferon production in coeliac disease as a response to gliadin peptides. Biochim Biophys Acta. 1226: 126-130.
 
[23]  Cornell H.J. &Wills-Johnson G. (2001). Structure-activityrelationships in coeliac-toxic gliadin peptides. Amino Acids. 21: 243-253.
 
[24]  Sturgess, R., Day P., Ellis H.J., Lundin K.E., Gjertsen,H.A., Kontakou M. & Ciclitir, P.J. (1994).Wheat peptide challenge in coeliac disease. Lancet. 343: 758-761.
 
[25]  McLachlan A., Cullis, P.G., Cornell, H.J. (2002). The use of extended motifs for focussing on toxic peptides in coeliac disease. J. Biochem. Mol. Biol. Biophys. 6: 319-324.
 
[26]  Cornell H.J. (1998). Partial in vitro digestion of active gliadin-related peptides in coeliac disease. J Protein Chem. 17: 739-744.
 
[27]  Cornell H.J. & Townley R.R.W. (1973). Investigating possible intestinal peptidase deficiency in coeliac disease. Clin Chim Acta..43: 113-125.
 
[28]  Cornell H.J., Doherty W. & Stelmasiak T. (2010). Papaya enzymes capable of detoxification of gliadin. Amino Acids. 38: 165-175.
 
[29]  Stepniak D, Spaenij-Dekking L, Mitea C, Moester M, de Ru A, Baak-Pablo R, van Veelen P, Edens L & Konig F. (2006). Highly efficient gluten degradation with newly identified prolyl endopeptidase: implications for celiac disease. Am. J, Physiol. Gastrointest. Liver Physiol. 291: G621-629.
 
[30]  Cornell H.J. & Stelmasiak T. (2011) Caricain - a basis for enzyme therapy for coeliac disease. Sth Afr J Sci..9/10: 107-111.
 
[31]  Zerhovni S, Amrani M, Nijs M, Smolders N, Azarkan M, Vincentelli J & Loose Y. (1998) Purification and characterisation of papaya cyclotransferase, a plant enzyme highly resistant to chemical, acid and thermal denaturation. Biochimica et Biophysica Acta. 1387: 275-290.
 
[32]  Janssen G, Christis C, Kooy-Winkelaar Y, Edens L, Smith D and van Veelen P. (2015) Ineffective degradation of immunogenic gluten epitops by currently available digestive enzyme supplements. PLOS ONE.
 
[33]  Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green P, Verna E C, Volta U, Alaedini A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease Gut.
 
[34]  Graf L, Horvath K, Walez E, Beazetei I and Burnier J. (1987) Effect of two synthetic α-gliadin peptides on lymphocytes in celiac disease: identification of a novel class of opioid receptors. Neuropeptides. 9:113-122.