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Review
. 2024 Apr 12;16(2):189-218.
doi: 10.1007/s12551-024-01188-4. eCollection 2024 Apr.

An overview on glycation: molecular mechanisms, impact on proteins, pathogenesis, and inhibition

Ana Belén Uceda  1 , Laura Mariño  1 , Rodrigo Casasnovas  1 , Miquel Adrover  1
Affiliations
Review

An overview on glycation: molecular mechanisms, impact on proteins, pathogenesis, and inhibition

Ana Belén Uceda et al. Biophys Rev. .

Abstract

The formation of a heterogeneous set of advanced glycation end products (AGEs) is the final outcome of a non-enzymatic process that occurs in vivo on long-life biomolecules. This process, known as glycation, starts with the reaction between reducing sugars, or their autoxidation products, with the amino groups of proteins, DNA, or lipids, thus gaining relevance under hyperglycemic conditions. Once AGEs are formed, they might affect the biological function of the biomacromolecule and, therefore, induce the development of pathophysiological events. In fact, the accumulation of AGEs has been pointed as a triggering factor of obesity, diabetes-related diseases, coronary artery disease, neurological disorders, or chronic renal failure, among others. Given the deleterious consequences of glycation, evolution has designed endogenous mechanisms to undo glycation or to prevent it. In addition, many exogenous molecules have also emerged as powerful glycation inhibitors. This review aims to provide an overview on what glycation is. It starts by explaining the similarities and differences between glycation and glycosylation. Then, it describes in detail the molecular mechanism underlying glycation reactions, and the bio-molecular targets with higher propensity to be glycated. Next, it discusses the precise effects of glycation on protein structure, function, and aggregation, and how computational chemistry has provided insights on these aspects. Finally, it reports the most prevalent diseases induced by glycation, and the endogenous mechanisms and the current therapeutic interventions against it.

Keywords: Diabetic-related diseases; Glycation; Glycation inhibitors; Protein aggregation; Protein function; Protein structure.

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Conflict of interest statement

Competing interestsThe authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Protein glycosylation (left) and protein glycation (right). In the protein glycosylation, the carbohydrates can be attached either to an Asn (N-glycosylation) or to a Ser/Thr (O-glycosylation) residue. N-Glycosylation can be of three different patterns: (i) high mannose type; (ii) hybrid type; and (iii) complex type. In the O-glycosylation, the first carbohydrate bound to a Ser/Thr residue is a GlcNAc and after it, there is not a clear pattern, as many different types of carbohydrates have been found. Protein glycation starts with the reaction of a reducing sugar (mainly glucose) or an α-hydroxyaldehyde (which might come from glucose autoxidation) with the Lys/Arg side chains of long-life proteins. These reactions yield the formation of a heterogeneous set of compounds named as AGEs
Fig. 2
Fig. 2
Molecular mechanism corresponding to the formation of a Schiff base from the reaction between the primary amine of a protein (P) and the carbonyl group of glucose (top). Once the Schiff base is formed, it rearranges to form an Amadori product (bottom)
Fig. 3
Fig. 3
Scheme of different pathways of AGE formation. The reaction between the ε-amino group of Lys and the carbonyl group of glucose forms a Schiff base, which rearranges to form an Amadori product. Some Amadori products are converted to AGEs by the Hodge pathway, and others are oxidized and cleaved to form RCS. These RCS are also generated by the Wolff and Namiki pathways from glucose and Schiff base, respectively. These RCS can further react with proteins to generate AGEs
Fig. 4
Fig. 4
Chemical structure of the more relevant characterized AGEs: Nδ-(5-methyl-4-imidazolon-2-yl)-l-ornithine (MG-H1), 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2), 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3), Nε-carboxyethyl-lysine (CEL), N,N(-di(Nε-lysino))-4-methyl-imidazolium (MOLD), Nε-carboxymethyl-lysine (CML), pyrraline, pentosidine, argpyrimidine, and N.δ-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-l-ornithine (THP), glucosepane, and N(6)-(2-((4-ammonio-5-oxido-5-oxopentyl)amino)-5-(2,3,4-trihydroxybutyl)3,5-dihydro-4H-imidazol-4-ylidene)lysinate (DOGDIC)
Fig. 5
Fig. 5
Chemical structure of the most common biological reactive carbonyl species
Fig. 6
Fig. 6
Main endogenous mechanisms of detoxification against glycation. The glyoxalase system (A) plays a crucial role in degrading reactive dicarbonyl compounds, which serve as glycating agents. In addition, complementary alternative mechanisms (right) further contribute to the elimination of these harmful compounds. The proteasomal system (B) and autophagy (C) are mechanisms responsible for breaking down glycated proteins with compromised functionality or structure
Fig. 7
Fig. 7
Chemical structures of the most relevant inhibitors of glycation. The compounds labeled with a red circle ( formula image ) are those that can inhibit glycation through the protection of the amino groups that are prompt to be glycated. The compounds labeled with a blue circle ( formula image ) are those that can inhibit glycation via scavenging carbonyl compounds. The compounds labeled with a green circle ( formula image ) are those that can inhibit glycation via chelating metal cations that promote it. The compounds labeled with a purple circle ( formula image ) are those that can inhibit glycation via the neutralization of ROS. The compounds labeled with a yellow circle ( formula image ) are those that can act as AGE breakers
See this image and copyright information in PMC

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