Abstract Title

The Role of Glucose Metabolites in the Non-Enzymatic Glycation of Human Hemoglobin (HbA)

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Organic Chemistry

Abstract

In the investigation of the molecular basis for diabetes mellitus, the most studied process is the non-enzymatic glycation (NEG) of human hemoglobin (HbA). In NEG, the initially-bound glucose is ring closed (RC) and must ring open (RO) while bound to generate an electrophilic aldehyde that proceeds in the glycation process. This process consists of the formation of a Schiff base, which can proceed to an Amadori intermediate and generate an array of advanced glycation end products (AGE) that result in a structurally-modified protein which may induce a pathology (e.g. diabetes mellitus). Inorganic phosphate (Pi) is known to accelerate the overall glycation process, but this is not the only role for Pi. The anion can also react with RC glucose prior to glucose binding and subsequently generate glucose metabolites. These metabolites can potentially bind to HbA and contribute to the glycation process. The role of Pi-mediated glucose metabolism on NEG is investigated by computational modeling and NMR spectroscopy. Pi can enhance ring opening of glucose prior to binding and then act as a base to generate metabolites. These metabolites can then bind to proteins and play a role in the glycation process.

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The Role of Glucose Metabolites in the Non-Enzymatic Glycation of Human Hemoglobin (HbA)

In the investigation of the molecular basis for diabetes mellitus, the most studied process is the non-enzymatic glycation (NEG) of human hemoglobin (HbA). In NEG, the initially-bound glucose is ring closed (RC) and must ring open (RO) while bound to generate an electrophilic aldehyde that proceeds in the glycation process. This process consists of the formation of a Schiff base, which can proceed to an Amadori intermediate and generate an array of advanced glycation end products (AGE) that result in a structurally-modified protein which may induce a pathology (e.g. diabetes mellitus). Inorganic phosphate (Pi) is known to accelerate the overall glycation process, but this is not the only role for Pi. The anion can also react with RC glucose prior to glucose binding and subsequently generate glucose metabolites. These metabolites can potentially bind to HbA and contribute to the glycation process. The role of Pi-mediated glucose metabolism on NEG is investigated by computational modeling and NMR spectroscopy. Pi can enhance ring opening of glucose prior to binding and then act as a base to generate metabolites. These metabolites can then bind to proteins and play a role in the glycation process.