Intracellular and extracellular proteins can potentially undergo nonenzymatic glycation (NEG), resulting in structural modification. This may change the function of the protein, leading to pathology. The majority of studies designed to understand NEG involve the reaction of glucose with human hemoglobin, HbA. NEG can be viewed as a four-stage process. These stages are: 1) reversible, non-covalent binding of a ring-closed glucose isomer that reversibly ring opens to a transient acyclic isomer; 2) a reaction between the bound, transient, ring-opened, electrophilic glucose isomer and nucleophilic amine residues (e.g., N-terminal α-amino groups and internal lysines) to generate a covalently-bound Schiff base; 3) rearrangement of the Schiff base to an Amadori intermediate (amino-1-deoxyfructose); and 4) the non-reversible formation of advanced glycation end products (AGE). In the first step, inorganic phosphate (Pi) can concomitantly bind with ring-closed glucose and serve as a base to ring open the cyclic glucose to yield the bound electrophilic ring-opened aldehydic isomer. Thus, Pi participates in stage 1. In the transition to the second stage, a nucleophilic amino acid residue attacks the electrophilic ring-opened glucose and after multiple acid/base steps generates a Schiff base. As an experimental validation of this process, taurine (a model for the nucleophilic amino acid residue) was reacted with glyceraldehyde (a model for the Pi-catalyzed electrophilic ring-opened glucose) and was found (via NMR spectroscopy) to generate a Schiff base. Computational assessment of the acid/base steps that follow the nucleophilic attack predicts that Pi participation occurs. The prevailing perspective has been that glycation rate enhancement by Pi is manifest in either the transition from Stage 2-Stage 3 and/or Stage 3-Stage 4. This work indicates that Pi participates in the transition Stage 1-Stage 2 of the NEG mechanism must also be considered.

Towards an understanding of nonenzymatic glycation #6: The role of inorganic phosphate in the transition from the non-covalent to covalent stage of glycation

251st National Meeting (2016)

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