Acetaldehyde is a physiological species existing in blood. Glyceraldehyde is a commonly-used surrogate for glucose in studies of nonenzymatic glycation. Both species exist in dynamic equilibrium between two forms, an aldehyde and a hydrate. Nonenzymatic covalent protein modification (NECPM) is a process whereby a protein is covalently modified by a non-glucose species. The purpose here is to elucidate the NECPM mechanism(s) for acetaldehyde and glyceraldehyde with human hemoglobin (HbA). For the first time, both aldehydic and hydrate forms of acetaldehyde and glyceraldehyde are considered. Computations and model reactions followed by <sup>1</sup>HNMR were employed. The aldehyde and hydrate forms of acetaldehyde bind and covalently-modify Val1 of HbA via different mechanisms, yet generate an identical protonated Schiff base (PSB). The aldehyde and hydrate of glyceraldehyde covalently-modify Val1 via mechanisms distinct from one another, yet generate an identical PSB. The PSB from acetaldehyde and glyceraldehyde possess different structures. The PSB from acetaldehyde is proposed to proceed to covalent-adducts that have been implicated in alcohol toxicity. Conversely, the PSB generated from glyceraldehyde can form an Amadori which has been implicated in diabetic complications. Thus, the PSB structure may be central to pathophysiological outcomes because it determines the structure of the stable covalent adduct formed.

New evidence for the diversity of mechanisms and protonated Schiff bases formed in the non-enzymatic covalent protein modification (NECPM) of HbA by the hydrate and aldehydic forms of acetaldehyde and glyceraldehyde

2019 Spring National Meeting

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