Gunnar Reiske/Sandbox 102: Difference between revisions
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== Treatments == | == Treatments == | ||
Prolyl endopeptidases (PEPs) are a family of serine protease enzymes that help accelerate the breakdown of proline residues in peptides. Since gluten is a proline-rich complex, these enzymes can be used to help treat individuals with celiac disease. <ref> Shan, L., I. I. Mathews, and C. Khosla. "Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Interdomain Dynamics in Catalysis and Specificity." Proceedings of the National Academy of Sciences 102.10 (2005): 3599-604. Web.</ref> | |||
A study was done to explore the structural features of two bacterial PEPs, one with a bound enzyme and one without (Figure 1). Both PEPs have two domains: one that is the catalytic binding site and one called the propeller domain. With further investigation of domain features of the PEP isolated from Myxococcus xanthus, interactions were observed that give the enzyme its proline-cleaving properties (Figure 2). | |||
Using the structural components of the open and bound forms of PEP enzymes, a mechanism was proposed in which the incoming proline-rich peptide causes a conformational change that opens the catalytic binding site. This conformation is stabilized by the prolines in the substrate interacting with the arginine and aspartate residues in the binding site. The propeller region does not interact with the bound substrate, but the aspartates and glutamate residues interact with arginine residues in the catalytic region to stabilize the unbound form of the enzyme. | |||
Bacterial PEPs can detoxify immunotoxic proline-rich peptides in gut lumen of celiac patients by breaking down the gliadin before it reaches the small intestines. Given orally as a therapeutic treatment for those with celiac disease. Further research would need to be done on how we can make these enzymes more acid-stable to withstand the acidic environment of the human intestine. <ref>Shan, L., I. I. Mathews, and C. Khosla. "Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Interdomain Dynamics in Catalysis and Specificity." Proceedings of the National Academy of Sciences 102.10 (2005): 3599-604. Web.</ref> | |||
Studies have been done to determine the feasibility of the therapeutic implementation of bacterial PEP’s for detoxification of gliadin complexes in individuals with celiac disease. The study showed that a substantially high concentration of PEP’s as well as long exposure times (3 hours) were required for a complete detoxification of gliadin peptides and thus prevent intestinal transport of the peptides. <ref>Matysiak-Budnik, T., Candalh, C., Cellier, C., Dugave, C., Namane, A., Vidal-Martinez, T., . . . Heyman, M. (2005). Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease. Gastroenterology,129(3), 786-796. doi:10.1053/j.gastro.2005.06.016</ref> | |||
== Structural highlights == | == Structural highlights == | ||