Towards understanding the role of organic phosphate in diabetes mellitus

The goal of this research is to understand the role of organic phosphates in the initial step of the nonenzymatic glycation process which is related to diabetes mellitus. In protein glycation, the initially bound ring closed glucose must ring open while bound to generate an electrophile that can react with a nucleophilic lysine or an N-terminal residue to form a covalently-bound Schiff base. The Schiff base can proceed to an Amadori intermediate, which then is able to generate advanced glycation end products. This results in a structurally-modified protein that may induce pathology. Glucose-6-phosphate (G6P) and 2,3-bisphosphoglycerate (BPG) are organic phosphates that are glucose metabolites produced in erythrocytes by glycolysis. They are known to accelerate the glycation by facilitating the ring opening of glucose and bind to known glycation sites. Computational modeling and nuclear magnetic resonance (NMR) spectroscopy were used to assess pre-Amadori mechanistic possibilities of organic Pi with implications for model proteins. In addition, purified bovine hemoglobin and albumin were incubated with G6P and BPG to advance understanding under physiological conditions