Evaluation of Nonenzymatic Posttranslational Modification–Derived Products as Biomarkers of Molecular Aging of Proteins

Abstract

BACKGROUND During their biological life, proteins are exposed in a cumulative fashion to irreversible nonenzymatic, late posttranslational modifications that are responsible for their molecular aging. It is now well established that these damaged proteins constitute a molecular substratum for many dysfunctions described in metabolic and age-related diseases, such as diabetes mellitus, renal insufficiency, atherosclerosis, or neurodegenerative diseases. Accordingly, the specific end products derived from these reactions are considered potentially useful biomarkers for these diseases. CONTENT The aim of this review is to give an overview of nonenzymatic posttranslational modifications of proteins and their influence in vivo, take inventory of the analytical methods available for the measurement of posttranslational modification–derived products, and assess the potential contribution of new technologies for their clinical use as biological markers of protein molecular aging. SUMMARY Despite their clinical relevance, biomarkers of posttranslational modifications of proteins have been studied only in the context of experimental clinical research, owing to the analytical complexity of their measurement. The recent implementation in clinical chemistry laboratories of mass spectrometry–based methods that provide higher specificity and sensitivity has facilitated the measurement of these compounds. These markers are not used currently by clinicians in routine practice, however, and many challenges, such as standardization, have to be confronted before these markers can be used as efficient tools in the detection and monitoring of long-term complications of metabolic and age-related diseases.

Development of Diagnostic Fragment Ion Library for Glycated Peptides of Human Serum Albumin: Targeted Quantification in Prediabetic, Diabetic, and Microalbuminuria Plasma by Parallel Reaction Monitoring, SWATH, and MSE

“…Similar to HSA modification by malondialdehyde (42), a highly positive local environment expedites glycation reaction, determining the site specificity of glycation. Recent studies that report the structural and biological impacts of albumin glycation also clearly indicate the plausi- bility of glycated albumin to be used as a specific marker for diabetes (43).…”

A history of HbA1c through Clinical Chemistry and Laboratory Medicine

“…In the early 1980s, glycation was demonstrated to progress continuously, especially in proteins with long half-lives (e.g., skin collagen [37] ), and to form, mainly by oxidative processes (the general process being referred to as glycoxidation), complex products called Advanced Glycation End Products (AGEs), suspected to participate in degenerative long-term complications of diabetes mellitus and other chronic diseases [38] . The structure of many of these components, their pathophysiological roles and their use as biomarkers have been established [39] . They corresponded to the Maillard products, described in 1912 in food industry when reducing sugars were heated with amino acids or proteins during sterilization processes [40] .…”

Serum Fluorescent Advanced Glycation End (F-AGE) products in gestational diabetes patients

“…AGEs constitute a large, complex, and heterogeneous group of molecules, and only some structures have been identified (1,16). ε N-carboxymethyl-lysine (CML), pentosidine, and methylglyoxal derivatives are examples of well-characterized AGEs (4,16).…”

“…AGEs constitute a large, complex, and heterogeneous group of molecules, and only some structures have been identified (1,16). ε N-carboxymethyl-lysine (CML), pentosidine, and methylglyoxal derivatives are examples of well-characterized AGEs (4,16). High performance liquid chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and fluorescence spectroscopy have been used to measure the concentrations of the different types of AGEs (17)(18)(19).…”