Gluten Be Gone: Synthetic Biology Solution for Celiac Disease
What is Celiac Disease? Celiac disease or gluten allergy comes from eating wheat, rye or barley. Most common in people of N. European descent, the symptoms include diarrhea, weight loss and an increased risk of cancer.
Why is gluten allergenic? Gluten contains an unusual protein called alpha gliadin, which has many repeats of the amino acids Proline and Glutamine (PQ motifs) that are resistant to the digestive enzymes in our stomach. In some people, these PQ-rich fragments cause severe allergy and inflammation.
Clinical trials: A natural bacterial enzyme from Sphingomonas capsulata that can break down PQ motifs is in clinical trials as an Oral Enzyme Therapeutic. But it works poorly in the acidic compartment of our stomach, and attempts to engineer it to become acid tolerant have not worked.
Trial by Acid: Univ. Washington undergraduates tackled the problem from the opposite direction. They found an enzyme called Kumamolysin-AS in a heat and acid loving bacterium Alicyclobacillus sendaiensis that was already acid tolerant. They tinkered with it, using the Fold-It protein folding game, until they found variants predicted to change the enzyme’s preference from Proline Arginine (PR) to Proline Glutamine (PQ). When they made and tested ~260 engineered enzymes, they found one that had a 116-fold increase in ability to digest the gluten peptide in acidic conditions, with a switch in preference of 800-fold! The new enzyme, KumaMAX, could be used in oral therapy or engineered into common bacteria found in yogurt to make probiotics.
So Much Win!: This work (1) could help millions of gluten allergy sufferers world wide, (2) was done by undergraduates competing in iGEM, an annual synthetic biology competition originally founded at MIT, (3) using gaming software, (4) built on basic research done on an obscure bacterial enzyme, and (5) published with student authors in a peer-reviewed journal.
Images: Normal catalytic triad of protease enyzmes (left) and acid tolerant substitution (right) found in bacteria growing in acid, hot springs (middle).
Paper: Computational Design of an α‑Gliadin Peptidase; Gordon et al., (2012) JACS 134, 20513−20520
Team UW iGEM: http://goo.gl/vgvTX