Abstract
This perspective focuses on illustrating the underappreciated connections between reactive carbonyl species (RCS), initial binding in the nonenzymatic glycation (NEG) process, and nonenzymatic covalent protein modification (here termed NECPM). While glucose is the central species involved in NEG, recent studies indicate that the initially-bound glucose species in the NEG of human hemoglobin (HbA) and human serum albumin (HSA) are non-RCS ring-closed isomers. The ring-opened glucose, an RCS structure that reacts in the NEG process, is most likely generated from previously-bound ring-closed isomers undergoing concerted acid/base reactions while bound to protein. The generation of the glucose RCS can involve concomitantly-bound physiological species (e.g., inorganic phosphate, water, etc.); here termed effector reagents. Extant NEG schemes do not account for these recent findings. In addition, effector reagent reactions with glucose in the serum and erythrocyte cytosol can generate RCS (e.g., glyoxal, glyceraldehyde, etc.). Recent research has shown that these RCS covalently modify proteins in vivo via NECPM mechanisms. A general scheme that reflects both the reagent and mechanistic diversity that can lead to NEG and NECPM is presented here. A perspective that accounts for the relationships between RCS, NEG, and NECPM can facilitate the understanding of site selectivity, may help explain overall glycation rates, and may have implications for the clinical assessment/control of diabetes mellitus. In view of this perspective, concentrations of ribose, fructose, Pi, bicarbonate, counter ions, and the resulting RCS generated within intracellular and extracellular compartments may be of importance and of clinical relevance. Future research is also proposed.
Highlights
Reactive carbonyl species (RCS) are electrophiles containing one or more carbonyl functional groups, typically aldehydes and/or ketones, which are present under physiological conditions
Results from human serum albumin (HSA) (Wang et al, 2013) illustrate that the initially-bound glucose species are the non-reactive carbonyl species (RCS) ring-closed isomers that ring open once bound. This observation was confirmed by Clark et al (2013) for glucose interactions with HbA and is consistent with studies of glucose and other monosaccharides binding to several enzymes (D-xylose isomerase, Lee et al, 1990; Allen et al, 1994; galactose mutarotase, Thoden et al, 1994; and phosphoglucoseisomerase, Lee and Jeffrey, 2005)
The direct binding of the ring-opened isomer of glucose in nonenzymatic glycation (NEG) is very unlikely because the equilibrium concentration of glucose in the ring-opened form in aqueous solution is 0.002% (Hayward and Angyal, 1977; Bunn and Higgins, 1981), corresponding to a concentration of just 0.12 μM in human plasma/serum
Summary
Reactive carbonyl species (RCS) are electrophiles containing one or more carbonyl functional groups, typically aldehydes and/or ketones, which are present under physiological conditions. The transient ring-opened glucose RCS isomer reacts nonenzymatically with intracellular and extracellular proteins to form glycated proteins, both in vivo (Bookchin and Gallop, 1968; Bunn et al, 1975) and in vitro (Baynes et al, 1989) over prolonged periods of time (weeks to months) via a multireaction process termed non-enzymatic glycation (NEG). For this perspective, we define the NEG process as the four stage process that involves the initial binding of glucose, followed by Schiff base formation, Amadori formation, and the formation of AGE. These findings are not reflected in historic or even in recent NEG schemes (Rodwell et al, 2015; Welch et al, 2016)
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