3.3.2 Net loss of connectivity in Pancriatic α-amylase protein when bound to inhibitor
The porcine pancreatic α-amylase protein (PPA) that is secreted by pancreatic acinar cells is responsible for the catalysing the initial step in starch hydrolysis and is an essential enzyme for producing glucose. Function of the protein is the endohydrolysis of (1-4)-alpha-D-glucosidic linkages in polysaccharides containing three or more (1-4)-alpha-linked D-glucose units. This is performed when the carboxylic oxygens of the catalytically competent residues Glu233 and Asp300 make hydrogen bonds with the “glycosidic” NH group of the acarviosine group. This protein is a major component of pancreatic fluid making it the primary target for the treatment of type 2 diabetes. Also, its interaction with several inhibitors is well documented as it is studied from perspective of several different diseases.
In our case study, the protein is bound to the microbial inhibitor tendamistat (PDB ID 1BVN shown in Supplementary Figure 3B). This bound form has the same topological fold as the unbound PPA however their network is found to be altered. A net loss of hubs and edges is observed along with loss of essential connectivity around the active site residue, 233E which functions as a proton donor. Most of the lost edges are found in the C-terminal domain of the proteins which binds to the tedamistat inhibitor where, 17 hubs are lost, of which one is an active site and only four hubs are gained (Figure 2B). Hence, the connectivity in the functional C-terminal domain is lowered when bound to the inhibitor which also blocks the active site of protein from performing hydrolysis.