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Non-enzymatic glycation (a.k.a. Maillard reaction) is a series of random spontaneous reactions between reducing sugars and amines, resulting in the formation of irreversible advanced glycation endproducts (AGE's). In food chemistry, this process is beneficial by contributing to the flavor, aroma, texture, and appearance of cooked foods. In vivo , however, Maillard reaction is deleterious because uncontrolled modification and crosslinking of biological macromolecules impairs their function. Consequently, chronic hyperglycemia of diabetes mellitus, for instance, leads to increased non-enzymatic glycation and diverse, multi-organ pathologies of diabetic complications. Based on the fact that toxic compounds, such as free radicals, are detoxified in vivo by specific defense mechanisms, one would expect to find mechanisms to control glucose toxicity as well. Thus far, only one such enzyme, fructosamine-3-kinase (FN3K), has been characterized. It operates intracellularly by catalyzing ATP-dependent removal of Maillard adducts, D-fructoselysines, from proteins, thereby reducing the Maillard reaction flux from glucose to AGE's. When FN3K was isolated, a closely related but distinct protein copurified with it. Unlike FN3K, however, this enzyme, fructosamine-3-kinase-related protein (FN3KRP), does not phosphorylate D-fructoselysines but it does phosphorylate several other (non-physiological) substrates. Interestingly, the distribution of FN3KRP in nature appears to be nearly universal whereas that of FN3K is limited to endotherms. In this article, it is suggested that the function of FN3KRP is deglycation of Maillard adducts downstream from fructoselysines. Such a mechanism, if proven correct, would be valuable given reports on apparent correlations between FN3KRP and some chronic conditions and/or diseases, such as a recent publication which proposes that the FN3KRP gene may be a longevity gene.

It took over 30 years for first description of the synthesis of fructosamines and this was conducted through non-enzymatic protein-glucose reactions (also known as glycation). Fructosamines in mammalian cells has not been known until recently. It transforms spontaneously into advanced glycation end products. The discovery of fructosamine 3-kinase, which is a novel enzyme, in human reveals the existence of a previously unknown intracellular metabolism of these substances. Protein-bound fructosamines are phosphorylated by fructosamine 3-kinase with high affinity on a third carbon atom of the deoxyfructose moiety and this results in fructosamine 3-phosphates. These later substances are unstable and spontaneously break down into inorganic phosphate and 3-deoxyglucosone, regenerating the unglycated amine in the process. The fact that many prokaryotic and eukaryotic genomes contain proteins connected to fructosamine 3-kinase shows that this 'deglycation' process is not exclusive to mammals. The current study aims at determining the normal values of fructoseamine 3-kinase enzyme in the control group as well as in the group of patients with type II diabetes (the experimental group). The relationship of enzyme activity with some biochemical variables was also studied in patients with type 2 diabetes, due to the association of these variables with high blood sugar, as shown by previous studies. The Research dealt with the investigation of Fructosamine 3-Kinase activity and some biochemical variables for (136) Type 2 diabetes patients. The results indicated that there was significant increase in Fructosamine 3-Kinase activity in type 2 diabetes patients (253 ng/l) in comparison to the control group. The normal value of enzyme in the control group was (181ng/l) and the activity of the enzyme in control group individuals was not affected by age and sex. The research also showed a significant decrease in the level of iron, zinc, chromium and sodium as well as a significant increase in the potassium level in patients with type 2 diabetes compared to the control group individuals. Additionally, the research predicted that there is a significant decrease in the levels of vitamins C and E. Also, it was shown that there was a significant increase in malondialdehyde level and a myeloperoxidase activity in type 2 diabetes patients. Activity of FN3K increased in type 2 diabetes compared to the control group individuals. It was noted that the activity of FN3K in the control group was not affected by age or sex. [ABSTRACT FROM AUTHOR]

Protein deglycation, a new form of protein repair, involves several enzymes. Fructosamine-3-kinase (FN3K), an enzyme found in mammals and birds, phosphorylates fructosamines on the third carbon of their sugar moiety, making them unstable and causing them to detach from proteins. This enzyme acts particularly well on fructose-epsilon-lysine, both in free form and in the accessible regions of proteins. Mice deficient in FN3K accumulate protein-bound fructosamines and free fructoselysine, indicating that the deglycation mechanism initiated by FN3K is operative in vivo. Mammals and birds also have an enzyme designated 'FN3K-related protein' (FN3KRP), which shares ≈65% sequence identity with FN3K. Unlike FN3K, FN3KRP does not phosphorylate fructosamines, but acts on ribulosamines and erythrulosamines. As with FN3K, the third carbon is phosphorylated and this leads to destabilization of the ketoamines. Experiments with intact erythrocytes indicate that FN3KRP is also a protein-repair enzyme. Its physiological substrates are most likely formed from ribose 5-phosphate and erythrose 4-phosphate, which give rise to ketoamine 5- or 4-phosphates. The latter are dephosphorylated by 'low-molecular-weight protein-tyrosine-phosphatase-A' (LMW-PTP-A) before FN3KRP transfers a phosphate on the third carbon. The specificity of FN3K homologues present in plants and bacteria is similar to that of mammalian FN3KRP, suggesting that deglycation of ribulosamines and/or erythrulosamines is an ancient mechanism. Mammalian cells contain also a phosphatase acting on fructosamine 6-phosphates, which result from the reaction of proteins with glucose 6-phosphate. [ABSTRACT FROM AUTHOR]

The purpose of this work was to identify the function of bacterial homologues of fructosamine 3-kinase (FN3K), a mammalian enzyme responsible for the removal of fructosamines from proteins. FN3K homologues were identified in ≈ 200 (i.e. ≈ 27%) of the sequenced bacterial genomes. In 11 of these genomes, from phylogenetically distant bacteria, the FN3K homologue was immediately preceded by a low-molecular-weight protein -tyrosine-phosphatase (LMW-PTP) homologue, which is therefore probably functionally related to the FN3K homologue. Five bacterial FN3K homologues (from Escherichia coli, Enterococcus faecium, Lactobacillus plantarum, Staphylococcus aureus and Thermus thermophilus) were overexpressed in E. coli, purified and their kinetic properties investigated. Four were ribulosamine/erythrulosamine 3-kinases acting best on free lysine and cadaverine derivatives, but not on ribulosamines bound to the alpha amino group of amino acids. They also phosphorylated protein-bound ribulosamines or erythrulosamines, but not protein-bound fructosamines, therefore having properties similar to those of mammalian FN3K-related protein. The E. coli FN3K homologue (YniA) was inactive on all tested substrates. The LMW-PTP of T. thermophilus, which forms an operon with an FN3K homologue, and an LMW-PTP of S. aureus (PtpA) were overexpressed in E. coli, purified and shown to dephosphorylate not only protein tyrosine phosphates, but protein ribulosamine 5-phosphates as well as free ribuloselysine 5-phosphate and erythruloselysine 4-phosphate. These LMW-PTPs were devoid of ribulosamine 3-phosphatase activity. It is concluded that most bacterial FN3K homologues are ribulosamine/erythrulosamine 3-kinases. They may serve, in conjunction with a phosphatase, to deglycate products of glycation formed from ribose 5-phosphate or erythrose 4-phosphate. [ABSTRACT FROM AUTHOR]