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.