Biology and the Maillard Reaction: Background
(Contribution from Dr Ben Szwergold)
Most, perhaps all, living cells and organisms depend on monosaccharides such as glucose as a source of energy and carbon for metabolism. Since reducing sugars, both aldoses and ketoses, are intrinsically reactive with primary and secondary amines (see an illustration of the initial of the reaction between glucose and lysine in Fig. 1), non-enzymatic glycation (Maillard reaction) is an unavoidable “background” reaction in all living systems dependent on its rate primarily on the concentration of the reagents, temperature and ionic milieu in which the reaction is occurring.
Figure 1. Early glycation products (EGPs)
Preponderance of evidence gathered over the past several decades suggest strongly that uncontrolled Maillard reaction is detrimental to the function and integrity of biological systems. These adverse effects can be caused by the early glycation intermediates (EGPs), or the final Advanced Glycation Endproducts (AGEs) through a variety of mechanisms. These include, among others: production of oxygen free radicals from EGPs, impairment of enzyme functions, perturbations of signaling by peptide hormones, activation of AGEs specific receptors, crosslinking of structural proteins, impairment of protein recycling etc.
Because of these deleterious effects of Maillard reactions various organisms have developed strategies for coping with this ongoing and unrelenting stress, similar in some of its aspects to that due to oxygen in aerobic organisms.
The various defense strategies can be roughly divided into two categories; passive and active mechanisms.
1. Passive mechanisms
One such mechanism that seems to have been generally adapted evolutionary is the utilization of glucose as the primary source of carbon and energy. From the standpoint of non-enzymatic glycation this an optimal monosaccharide since, having an extremely low proportion of the open chain form it is the least reactive with amines among the known sugars (Bunn). Furthermore the concentration of glucose are very tightly regulated at 5 -10 mM by a continuous feedback mechanism consisting (in part) of pancreatic b-islet cells, liver and skeletal muscles and utilizing the counterbalancing effects of hormones such as insulin and glucagon.
Another mechanism utilized by some cells such as avian and pig erythrocytes is to forgo the direct utilization of glucose as a fuel utilizing instead compounds such as adenosine and/or inosine.
Finally, an ingenious mechanism utilized by most insects is to use as carrier of energy and carbons in their blood a non-reducing disaccharide, trehalose, which is broken down to glucose concomitantly with its transport into cells. Thus glycemic stress is reduced since there are virtually no reducing sugars in the hemolymph while in cells only as much glucose is taken up as needed and as can be metabolized.
2. Active mechanisms
These systems can be divided into two subdivisions: one dealing directly with glucose and its proximal metabolites and the other one operating on downstream products of glucose metabolism such as methylglyoxal (MG) and deoxyglucosone (3DG). This section will deal only with mechanisms operating on glucose and its proximal products. Discussion of MG and 3DG can be found elsewhere (hyperlink this to section on MG & 3DG) on this Web Page.
While not proven, the current postulate is that the first of these mechanisms involves transglycation of glucosylamines (and other Schiff's bases) by a variety of biological nucleophiles such as glutathione, amino acids, aminothiols and polyamines.
Figure 2. Hypothesis: transglycation of glucosylamines
This mechanism appears to be widespread in nature as evidenced by high concentrations of nucleophiles compounds such as free amino acids in insects and high levels of taurine in birds. Is widespread. For a more detailed discussion of this emerging mechanism go here (hyperlink to discussion of transglycation).
The second mechanism involves deglycation of ketosamines (Amadori) products by fructoselysine-3-phosphate (FN3K). The deglycating function has not yet been documented conclusively but all experimental results thus far indicate that this indeed is its function (refs) and that this FN3K and that activity of this enzyme is essential for cell viability.
In warm-blooded animals FN3K is accompanied by a very closely related isozyme, FN3K-related-protein (FN3KRP). Interestingly, FN3KRP does not phosphorylate fructoselysine and most other substrates of FN3K. Van Schaftingen et al have shown that this kinase can phosphorylate ribulosamines, erythrosamines and psicosamines. While this finding is of considerable experimental value, none of these substrates are likely to be of physiological importance since free ribose, erythrose and allose (a precursor of psicosamines) are found in cells in negligible amounts.
Since gene for FN3KRP (and closely related homologues) are widespread in nature present in most animals, plants and many microbes (except for insects and yeasts) this gene must play an important role in cell metabolism. What this role is remains unclear but it is reasonably safe to postulate that it involves deglycation of some, as yet unidentified Maillard products.