In a modular PKS such as the 6-deoxyerythronolide B synthase, sets of catalytic domains are organized into modules. The catalytic domains from a given module cooperate to synthesize polyketides via a thiotemplate mechanism similar to that of fatty acid synthesis. The nascent polyketide intermediates are then passed down to the next module in the protein assembly line. Organized into three polypeptides (DEBS1-3), DEBS consists of six catalytic modules, each containing a unique set of covalently linked catalytic domains. Together, the six modules of this megasynthase (approximated 2MDa) produce 6-deoxyerythronolide B (6-dEB), the polyketide portion of the antibiotic erythromycin.

Celiac Sprue (celiac disease, coeliac disease, and non-tropic sprue) is a common, lifelong disorder with an incidence of about 1:100. The disease results from both a food hypersensitivity and an autoimmune condition; genetically predisposed individuals suffer an intestinal inflammatory response to ingested gluten from wheat and related proteins from barley and rye. Long, proline-rich fragments of gluten survive digestion by luminal and brush-border enzymes; as a result, they are able to gain access to the lamina propria. Most gluten peptides that survive gastrointestinal breakdown are excellent substrates for transglutaminase 2 (TG2). The resulting deamidated products are recognized by CD4-positive T cells, when bound to Human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 molecules on the cell surface of antigen-presenting cells. Upon activation, gluten-reactive CD4-positive T cells produce interferon-gamma (IFN-gamma), which is a major Schematic depiction of factors that contribute to the development of celiac disease contributor to the development of the coeliac lesion; IFN-gamma is also produced by intra-epithelial T cells. Similarly, interleukin-15 (IL-15), produced by either mononuclear cells in the lamina propria or by enterocytes themselves, attracts T cells with the capacity to kill enterocytes. IL-15 production is stimulated by gluten in the intestine in coeliac disease. Finally, B cells receive help from T cells to differentiate into plasma cells, which then produce autoantibodies against TG2. Currently, the only treatment for Celiac Sprue is adherence to a strict gluten-free diet. Such a diet is difficult to maintain as gluten is the second most common food additive behind sucrose. Thus, there is an unmet need for alternative, nondietary therapies for coeliac disease.

Identifying the target and mechanism of action of a broad spectrum antiviral.