Abstract
Understanding the molecular basis of the disease is of the utmost scientific interest as it contributes to the development of targeted strategies of prevention, diagnosis, and therapy. Protein carbonylation is a typical feature of glyco-oxidative stress and takes place in health disorders such as diabetes. Allysine as well as its oxidation product, the α-amino adipic acid (α-AA) have been found to be markers of diabetes risk whereas little is known about the chemistry involved in its formation under hyperglycemic conditions. To provide insight into this issue, human serum albumin was incubated in the presence of FeCl3 (25 μM) and increasing glucose concentrations for 32 h at 37 °C. These concentrations were selected to simulate (i) physiological fasting plasma concentration (4 mM), (ii) pathological pre-diabetes fasting plasma concentration (8 mM), and pathological diabetes fasting plasma concentration (12 mM) of glucose. While both allysine and α-AA were found to increase with increasing glucose concentrations, the carboxylic acid was only detected at pathological glucose concentrations and appeared to be a more reliable indicator of glyco-oxidative stress. The underlying chemical mechanisms of lysine glycation as well as of the depletion of tryptophan and formation of fluorescent and colored advanced glycation products are discussed.
Highlights
The oxidative damage to proteins is an expression of the impairment of the redox status and typically takes place during oxidative stress, aging, and the onset of age-related diseases [1]
The formation of protein carbonyls is usually described as the result of a radical-mediated mechanism by which sensible alkaline amino acids undergo oxidative deamination to yield aldehydes, namely, the α-aminoadipic semialdehyde and the γ-glutamic semialdehyde [3]
It is worth highlighting that the radical-mediated pathway of protein carbonylation cannot be ruled out since the oxidative decomposition of glucose in the presence of transition metals such as iron leads to the formation of a variety of reactive oxygen species (ROS) and hydrogen peroxide [24]
Summary
The oxidative damage to proteins is an expression of the impairment of the redox status and typically takes place during oxidative stress, aging, and the onset of age-related diseases [1]. The reaction of reducing sugars and Maillard-derived dicarbonyls (i.e., glyoxal and methyl-glyoxal) with such alkaline amino acids have been found to lead to the formation of the aforementioned aldehydes [4] This Maillard pathway of protein carbonylation has recently been emphasized as remarkable compared to the radical-mediated mechanisms in conditions that simulate both physiological and food processing [5,6]. An intermediate compound in lysine metabolism, the α-aminoadipic acid (α-AA), has been surprisingly identified as a biomarker of insulin resistance and obesity [8] Earlier, this compound was identified as an early indicator of diabetes in a metabolomic study in humans and was found to induce such metabolic conditions in experimental animals after oral administration [9]. This study was designed to investigate the formation of allysine and α-AA in human serum albumin in the presence of increasing concentrations of glucose and assess the suitability of these species as reliable markers of the glyco-oxidative damage to human plasma proteins
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