Gang Liu, Dhananjay D. Marathe, and Sriram Neelamegham. Chemical and Biological Engineering, SUNY at Buffalo, 303 Furnas Hall, Buffalo, NY 14260
A key step during leukocyte recruitment to sites of inflammation involves binding of O-linked glycans decorated on the mucinous protein P-selectin Glycoprotein Ligand-1 (PSGL-1) to adhesion molecules belonging to the selectin family. The rates of such O-linked glycosylation are controlled by a family of enzymes called glycosyltransferases inside the cellular golgi. We applied both enzymology based experimental assays and mathematical modeling to understand better the concerted action of various glycosyltransferases in controlling the glycan structure on PSGL-1. In the computational model, glycosylation reactions were described as bimolecular chemical processes. Multiple well-mixed reaction compartments in series were considered in order to mimic the individual golgi compartments. Enzyme properties were defined in terms of donor sugar nucleotide, acceptor substrate specificity and location in golgi. Using the above information, defined starting material and glycosylation end products based on published literature, a library of reaction pathways were automatically generated. Genetic algorithms were then applied to fit the various glycosylation models. These models were scored and model parameters were compared to experimentally measured enzymatic rate constants. It is shown that the simulated glycan composition of multiple reaction networks agree well with experimental data. This systems level modeling approach can be used to generate experimentally testable hypothesis.