Reconsidering the role of protein glycation in disease

Abstract

Protein glycation has long-been considered a toxic consequence of carbohydrate metabolism. Yet recent evidence demonstrates tight regulation for these non-enzymatic post-translational modifications, pointing to a broader role in cell biology rather than simply serving as a biomarker for toxicity.

Fig. 1 ∣. Metabolic sources of protein glycation.

Non-enzymatic PTMs are derived from metabolic intermediates In glycolysis and the polyol pathway. Note the proposed mechanism of argpyrimidine formation and the metabolic source of 3-deoxyglucosone have not been fully determined.

Fig. 2 ∣. Methylglyoxal metabolism.

The bulk of MGO (~99%) is detoxified by the glyoxalase cycle, consisting of GLO1 and GLO2. Aldo-keto reductases (AKRs) and aldehyde dehydrogenases (ALDHs) also have a minor role in MGO metabolism, yielding hydroxyacetone and pyruvate, respectively. MGO, methylglyoxal; GSH, glutathione; LGSH, lactoylglutathione; HTA, hemithioacetal.

Fig. 3 ∣. Towards relevant study designs in protein glycation.

a, Hyperglycemic conditions mimic pathophysiologic concentrations of glycating agents. b, Clickable analogs of glycating agents can be used to monitor targets of protein glycation. These probes can be pulsed into cells, relying on endogenous metabolism to yield physiologically relevant concentrations and locations of the probes. c, Genetic manipulations (such as CRISPRi) provide local, controlled increases in reactive species. d, The use of non-natural amino acids (such as MG-H1 or fructosylLys) and genetic code expansion provides precise incorporation of PTMs on target proteins, yielding mechanistic insight into their role in enzyme function and cell fate.