Maillard reactions in biology have been studied for several decades and by now it is clear that in order to survive and function, living organisms have to control these reactions . To date almost all of the studies on Maillard reactions in-vivo were conducted in vertebrates . Interestingly, virtually no work has been done on anti-glycation defenses in “heat-loving” microorganisms such as thermophiles and hyperthermophiles.
Most pressing need for such anti-Maillard systems exists in Hyperthermophiles that live at temperatures ranging from 80oC to 120oC . To survive and thrive at these extreme temperatures, hyperthermophiles have evolved adaptive mechanisms that preserve the structures and functions of their proteins, nucleic acids and lipids . In contrast with macromolecules, the major metabolic pathways in hyperthermophiles are similar or identical to those of mesophiles. . Some intermediates of these pathways such as glucose-6-phosphate, glyceraldehyde-3-phosphate and fructose-1,6-bisphosphate are very potent glycating agents. .
Since, at hyperthermophiles temperatures, Maillard reactions are 100 to 10,000 times faster than at temperatures encountered by mesophiles (20 - 45oC) , life of such organism would be impossible without effective anti-Maillard defenses.
The objectives of this meta-review to examine the various anti-glycation strategies available to hyperthermophiles and to evaluate which of them may be relevant to hyperthermophiles.
This study analyzed published information relevant to Maillard reactions in hyperthermophiles. Since the number of known thermophiles and hyperthermophiles is more than 300, in order provide a sharp focus the review is restricted to 27 species of hyperthermophilic archaea: Desulfurococccales and Thermococcales, listed in Table 1.
The strategies available to cells to deal with the stress of Maillard reactions can be grouped into three categories:
A. Modifications of macromolecules to reduce or eliminate
susceptibility to non-enzymatic glycation
B. Repair and/or selective removal of macromolecules modified by
C. Prevention of glycation
Results of analysis regarding possible contribution of each of these strategies to the resistance of hyperthermophilic Archaea to glycation are summarized below.
A. Modifications of macromolecules to resist glycation
Proteins Based on a handful of studies that address this issue , it appears that proteins of hyperthermophiles do not possess any features that would make them less susceptible to glycation.
Nucleic acids Nucleic acids of hyperthermophiles are made of the same nucleosides as mesophiles and their sequences as well as G/C content are also very similar to mesophiles and thus offer no apparent advantage in resisting glycation.
Phospholipids Unlike proteins or nucleic acids, phospholipids of hyperthermophiles appear to be resistant to Maillard reactions by virtue of the fact that they do not contain any basic, glycation-susceptible head-groups such as ethanolamine .
B. Repair of glycation damage
Proteins Glycated and damaged proteins of hyperthermophiles are selectively degraded by several proteolytic mechanisms. One of the most widespread and perhaps most important of such systems is the glycopeptidase GcP .
Nucleic acids Hyperthermophiles have very active and sophisticated mechanisms of DNA repair . Presumably this includes an ability to repair glycation damage but this issue has not yet been specifically investigated.
Removal of Amadori and Heyns adducts None of the Archaea examined in this study contain any deglycating genes such as FN3K, FN3KRP or Amadoriases .
C. Prevention of glycation
Intracellular conditions The intracellular milieu of hyperthermophiles is very similar to that of mesophiles and thus offers no advantage to these organisms in their anti-Maillard defenses.
Modifications of metabolic pathways hypothetically, modifying metabolic pathways can reduce the variety and concentrations of glycating metabolic intermediates. Since this has not occurred, hyperthermophiles have the same number and levels of glycating metabolites as mesophiles .
Metabolite channeling Substrate channeling through multienzyme complexes appears to be used in hyperthermophiles to protect labile metabolites such as carbamoyl phosphate  and
it is reasonable to postulate that this mechanism is also used to minimize glycation.
Conversion of reactive sugars to inert compounds Hyperthermophiles rapidly convert reactive monosaccharides such as glucose to inert compounds that include trehalose, mannosylglycerate, diglycerol-phosphate and di-myo-inositol-phosphate [13,14].
Detoxification of -dicarbonyls While hyperthermophiles do not contain GSH and a glyoxalase system they do have enzymes such as glycerol dehydrogenases, methylglyoxal reductases and aldehyde dehydrogenases that efficiently detoxify -dicarbonyls
Scavenging of carbonyls and transglycation One of the unique features of hyperthermophiles is the high intracellular concentration of polyamines including some novel compounds such as long chain caldopentamine and caldohexamine and branched polyamines such as tris-(3-aminopropyl)amine [15-17] (Fig. 1).
Fig. 1. Structures of archaeal polyamines. Adapted from, ref. 15.
The concentration of polyamines in hyperthermophiles increase with temperature and these compounds are essential for cell viability and growth. Since polyamines are known to function as excellent scavengers of carbonyls and as transglycating agents it is likely that one of their main roles in hyperthermophiles is to be part of a defense system against Maillard reactions.
In-vitro incubations of reactive sugars and proteins at temperatures such as those experienced by hyperthermophiles result in rapid and massive production of AGE’s . It is therefore hard to overstate the crucial importance of defense mechanisms against Maillard reactions as a factor that enables hyperthermophiles to survive and thrive at temperatures that are lethal to all other forms of life.
My analysis suggests that hyperthermophilic Archaea uses five mechanisms to deal with the stress of Maillard reactions:
A. Their phospholipid head-groups are modified to exclude glycation-prone moieties such
B. In the absence of GSH and glyoxalases hyperthermophiles detoxify -
dicarbonyls using a variety of reductases and dehydrogenases
C. They channel metabolic intermediates from one enzyme to another
in multi-enzyme complexes.
D. They convert reactive monosaccharides to inert derivatives such as
E. They scavenge free dicarbonyls using a vast array of
These five mechanisms work synergistically to defend hyperthermophiles against Maillard stress and an absence of any one of them inhibits growth and can be lethal. However, only in hyperthermophiles are polyamines found at very high concentrations. This suggests that polyamines are uniquely important in allowing hyperthermophilic Archaea to withstand the increased Maillard stress at elevated temperatures [15-17]. This is accomplished by scavenging of free carbonyls and the breakdown of Schiff bases by transglycation.
If correct, this hypothesis suggests that supplementation of human diet with carbonyl scavengers could be beneficial in slowing down or preventing the formation of AGE’s. While increasing polyamine concentrations substantially in mammals is impractical and may even be toxic [19,20], increasing concentrations of other carbonyl scavengers such as carnosine and taurine is feasible and has already proven to be effective [21-22]. In addition to endogenous, amines-containing, carbonyl scavengers, there is data suggesting that a number of plant-derived polyphenols such as phlorotannins, phlorizin and phlorin can also be used to trap carbonyls [23,24]. This suggests that these types of compounds, which are already part of human diet, could be used as safe dietary supplements to control and slow down AGE formation in humans.
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