Disease relevance of FN3K

• The genes were expressed in all human tissues examined, with FN3K showing significantly higher levels in organs susceptible to nonenzymatic glycation and diabetic complications [1].
• Intrinsic toxicity of glucose, due to non-enzymatic glycation, is controlled in-vivo by deglycation systems including: FN3K-mediated deglycation of fructosamines and transglycation of aldosamines [2].
• In this perspective, small changes in flow rates in the spermine (where ODC and antizyme are key players) and/or FN-3-K pathway could contribute to enhance the effects of hyperglycemia and explain why there are diabetic subjects with higher glycation phenotypes and incidence of complications [3].

High impact information on FN3K

• Fructosamine-3-kinase (FN3K) is a recently described protein-repair enzyme responsible for the removal of fructosamines, which are the products of a spontaneous reaction of glucose with amines [4].
• Fructosamine 6-phosphates, which result from the reaction of amines with Glu-6-P, were not substrates for FN3K [4].
• The aim of this work was to identify the fructosamine residues on hemoglobin that are removed as a result of the action of FN3K in intact erythrocytes [5].
• In this report, we describe the purification and characterization of a mammalian fructosamine-3-kinase (FN3K), which phosphorylates fructoselysine (FL) residues on glycated proteins, to FL-3-phosphate (FL3P) [6].
• Because the condensation of glucose and lysine residues is an ubiquitous and unavoidable process in homeothermic organisms, a deglycation system mediated by FN3K may be an important factor in protecting cells from the deleterious effects of nonenzymatic glycation [6].

Biological context of FN3K

• Our results indicate that (1) both FN3K and FN3KRP promoters are TATA-less and CAAT-less and contain several homologous CpG islands and Sp1 binding sites [7].
• Fructosamine 3-kinase (FN3K), an enzyme initially identified in erythrocytes, catalyses the phosphorylation of fructosamines on their third carbon, leading to their destabilization and their removal from protein [8].
• This variability was stable with time and associated (P < 0.0001) with two single nucleotide polymorphisms in the promoter region and exon 6 of the FN3K gene [9].
• Human fructosamine-3-kinase: purification, sequencing, substrate specificity, and evidence of activity in vivo [6].
• The presence of proteins related to fructosamine 3-kinase in many prokaryotic and eukaryotic genomes suggests that this 'deglycation' process is not restricted to mammals [10].

Anatomical context of FN3K

• Cultured fibroblasts treated with conditions mimicking the hormonal and biochemical profile of the diabetic state showed no changes in FN3K and FN3KRP expression relative to untreated cells [1].
• Moreover, analysis of the fructoselysine 3-phosphate content of haemoglobin from diabetic subjects suggests that, in addition to FN3K, another deglycating mechanism may be operative in human erythrocytes [11].
• (4) Knockdown of FN3K in cultured cells inhibits or arrests their growth [7].

Associations of FN3K with chemical compounds

• These include, among others, the fact that while the apparent deglycation mechanism does not operate on L-glucose, semi-purified FN3K appears to be able to use both D- and L-fructosamines as substrates [11].
• NMR analysis indicated that 1-deoxy-1-morpholinopsicose (DMP, a substrate for FN3K and FN3K-RP), like 1-deoxy-1-morpholinofructose (DMF, a substrate of FN3K), penetrated erythrocytes and was converted into the corresponding 3-phospho-derivative [8].
• We postulate that this, FN3K-independent, deglycation occurs by transglycation, in which carbohydrate moieties of glycated amines, such as glucoselysines on proteins, are removed by intracellular nucleophiles including free amino acids and peptides such as glutathione, carnosine and anserine [2].
• Spermine and FN-3-K may be part of a carbonyl damage control pathway [3].
• We have purified and characterized Amadorase, a fructosamine-3-kinase, and demonstrated both in vitro and in vivo that it is responsible for the production of 3-deoxyglucosone (3DG) [12].

Other interactions of FN3K

• These data suggest that FN3K and FN3KRP act as protein repair enzymes and are expressed constitutively in human cells independently of some of the variables altered in the diabetic state [1].

References