The nonenzymatic glycation (NEG) of human hemoglobin (HbA) to hemoglobin A1c (HbA1c) is a well-accepted biomarker of glycemia and is elevated in patients with diabtes mellitus. The formation of HbA1c occurs at the end termini of β-chains of HbA and requires the ring-opening of a bound ring-closed glucose. Although inorganic phosphate (Pi) is known to accelerate the glycation process of several proteins, it is not known whether organic phosphates such as 2, 3-Bisphosphoglycerate (BPG) can perform similar acid/base chemistry and facilitate amino acid/ glucose, nucleophile/electrophile reactions. BPG occurs in high concentrations in human erythrocytes (~5 mmol L<sup>-1</sup>) and is known to bind deoxyhemoglobin by forming salt bridges with lysine and histidine residues near the N-termini of the β-chains. N-terminal valines in these sites are preferentially glycated and responsible for the formation of HbA1c. We hypothesize that BPG serves as a base and facilitates glucose ring-opening (forming the electrophile), and/or deprotonates valine1 amino acid residues (generating nucleophiles). Nuclear Magnetic Resonance (NMR) spectroscopy and computational modeling were used to determine the potential roles of BPG in the formation of HbA1c. Our results suggest that: 1) BPG can enhance glucose ring-opening in aqueous solution by a factor of 6 from model reaction followed by NMR, generating the necessary electrophile; 2) BPG can transiently and concomitantly bind (with favorable exothermicity and geometry) within 4 Å of both valine1 of the β-chains with ring-closed glucopyranose; and 3) BPG can also deprotonate valine1 to facilitate the nucleophile. In summary, similar to Pi, BPG serves as a physiological base and can play multiple mechanistic roles to facilitate the nonenzymatic formation of HbA1c in human erythrocytes.<br/>

Towards an understanding of nonenzymatic glycation #2: The role of 2, 3-bisphosphoglycerate in nonenzymatic glycation of human hemoglobin and formation of HbA1c

251st National Meeting (2016)

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