2.7.1.171	evolution	fructosamine-3-kinases belong to the large superfamily of protein kinase-like (PKL) enzymes. The strained disulfides in the dimeric Arabidosis thalina enzyme function as redox switches to reversibly regulate the activity and dimerization of FN3K. Human FN3K, which contains an equivalent P-loop Cys, is also redox sensitive, whereas ancestral bacterial FN3K homologues, which lack a P-loop Cys, are not. Redox control mediated by the P-loop Cys is an ancient mechanism of FN3K regulation that emerged progressively during FN3K evolution from bacteria to humans. Redox regulation seem to have evolved in FN3K homologues in response to changing cellular redox conditions	762465	
2.7.1.171	evolution	fructosamine-3-kinases belong to the large superfamily of protein kinase-like (PKL) enzymes. The strained disulfides in the dimeric Arabidosis thalina enzyme function as redox switches to reversibly regulate the activity and dimerization of FN3K. Human FN3K, which contains an equivalent P-loop Cys, is also redox sensitive, whereas ancestral bacterial FN3K homologues, which lack a P-loop Cys, are not. Redox control mediated by the P-loop Cys is an ancient mechanism of FN3K regulation that emerged progressively during FN3K evolution from bacteria to humans. Redox regulation seems to have evolved in FN3K homologues in response to changing cellular redox conditions	762465	
2.7.1.171	evolution	the FN3K gene may have arisen by an event of duplication of an ancestral gene, FN3K-related protein (FN3K-RP). The gene encoding FN3K-RP is located next to the one encoding FN3K, and share a 65% sequence homology with FN3K and an identical genome organization. Both FN3K and FN3K-RP phosphorylate psicosamines and ribulosamines, but only the former act on fructosamines	738073	
2.7.1.171	malfunction	FN3K CRISPR knockout alters redox-sensitive cellular metabolites	762465	
2.7.1.171	malfunction	Fn3k-/- mice look healthy and have normal blood glucose and serum fructosamine levels. Their level of haemoglobin-bound fructosamines is approx. 2.5-fold higher than that of control (Fn3k+/+) or Fn3k+/- mice. Other intracellular proteins are also significantly more glycated in Fn3k-/- mice in erythrocytes and in brain, kidney, liver and skeletal muscle, indicating that FN3K removes fructosamines from intracellular proteins in vivo	707426	
2.7.1.171	malfunction	mice deficient in FN3K accumulate protein-bound fructosamines and free fructoselysine, indicating that the deglycation mechanism initiated by FN3K is operative in vivo	707094	
2.7.1.171	malfunction	N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes. FN3K deficiency increases NRF2 glycation and impairs its ability to counter ROS stress in liver and lung cancer cells. Pre-treatment with the ROS scavenger and GSH precursor N-acetyl cysteine (NAC) reverses H2O2 and DLS toxicity and restores glutathione balance in FN3K-deficient HepG2 and H3255 cells, respectively. FN3K deficiency leads to increased proteasomal and MG132-sensitive degradation of the glycated NRF2 protein. Glycation also affects NRF2 function in KEAP1 mutant cells, for example gene and protein expression analyses of FN3K deficient and control Huh-1 liver cancer cells (KEAP1N414Y) show loss of NRF2 targets and resultant redox imbalance as indicated by increased glutathione oxidation	760823	
2.7.1.171	malfunction	polymorphisms of the FN3K gene are associated with variations in HbA1c levels and with the onset of type 2 diabetes mellitus (T2DM) and pathogenic mechanisms related to its complications, role of FN3K polymorphisms in the development of microvascular and macrovascular complications of diabetes, overview. The FN3K genotype presenting GG at position -385, TT at position -232, and CC at c.900 A, is associated with less severe microangiopathic and macroangiopathic complications as a whole, compared to all other genotypes	760800	
2.7.1.171	malfunction	removal of the chloroplast signal peptide results in the localization of AtFN3K in different cellular compartments, including nucleus and mitochondria. FN3K CRISPR knockout alters redox-sensitive cellular metabolites	762465	
2.7.1.171	malfunction	significant relationship of FN3K (rs1056534) and (rs3848403) polymorphisms with with endothelial dysfunction and concentration of soluble receptor for advanced glycation end-products (sRAGE) in patients with diabetes, clinical parameters, overview	739258	
2.7.1.171	metabolism	despite its ability to reduce the glycation of intracellular islet proteins, fructosamine-3-kinase is neither required for the maintenance of beta-cell survival and function under control conditions nor involved in protection against beta-cell glucotoxicity	707061	
2.7.1.171	metabolism	starvation and diabetes do not change the level of expression of FN3K in different tissues, and no regulation of FN3K expression is observed in human fibroblasts treated with condition mimicking the diabetic state	738073	
2.7.1.171	additional information	no correlations of enzyme activity with age, sex, body weight, blood cholesterol, or plasma glucose in an oral glucose tolerance test are observed. Subjects whose parents or siblings had a stroke show lower FN3K activity	738072	
2.7.1.171	additional information	the strained disulfides in the dimeric Arabidosis thalina enzyme function as redox switches to reversibly regulate the activity and dimerization of FN3K. Critical role for the ATP-binding P-loop in the redox regulation of FN3Ks. HsFN3K, in which the P-loop Cys is conserved, is redox-regulated and displayed altered oligomerization when proliferating cells are exposed to acute oxidative stress. Structure-function analysis, overview	762465	
2.7.1.171	additional information	the strained disulfides in the dimeric Arabidosis thalina enzyme function as redox switches to reversibly regulate the activity and dimerization of FN3K. Critical role for the ATP-binding P-loop in the redox regulation of FN3Ks. The P-loop is stabilized in an extended conformation by a Cys-mediated disulfide bond connecting two chains to form a covalently linked dimer in which the reduction of disulfides results in AtFN3K activation. Structure-function analysis, overview	762465	
2.7.1.171	physiological function	advanced glycation end-products are key players in pathogenesis of long-term vascular diabetes complications, several enzymes such as fructosamine 3-kinase (FN3K) and glyoxalase I (GLO I) are crucial in preventing glycation processes	739258	
2.7.1.171	physiological function	CS-0777, a candidate compound for autoimmune diseases, becomes phosphorylated to an active metabolite, M1, by fructosamine 3-kinase (FN3K) and FN3K-related protein (FN3K-RP, EC 2.7.1.172), and (2R)-2-amino-2-methyl-4-(1-methyl)-5-[4-(4-methylphenyl)butanoyl]-1H-pyrrol-2-yl)butyl dihydrogen phosphate is reverted back to CS-0777 by alkaline phosphatase (ALP) in the body	762516	
2.7.1.171	physiological function	FN3K serves as a protein repair enzyme and also in the metabolism of endogenously produced free fructose-epsilon-lysine. Repairing lysine residues may be important to restore enzymatic activity, protein–protein interaction or recognition sites for phosphorylation (which often comprise basic residues) or ubiquitinylation	707426	
2.7.1.171	physiological function	fructosamine 3 kinase is a deglycating enzyme, which may play a key role in reducing diabetes-induced organ damage by removing bound glucose from glycated proteins	738074	
2.7.1.171	physiological function	fructosamine 3-kinase (FN3K) is involved in protein deglycation FN3K phosphorylates fructosamines on the third carbon of their sugar moiety, making them unstable and causing them to detach from proteins, suggesting a protective role of this enzyme. FN3K is able to break down the second intermediate of the non-enzymatic glycation cascade by phosphorylating fructoselysine to a fructoselysine-3-phosphate. The variability in FN3K activity is associated with some polymorphisms in the FN3K gene, FN3K involvement in diabetes, overview. FN3K might act in concert with other molecular mechanisms and may impact on gene expression and activity of other enzymes involved in deglycation process	738073	
2.7.1.171	physiological function	fructosamine-3-kinase (FN3K) is a kinase that triggers protein deglycation. Transcription factor NRF2 activity depends on FN3K activity, NRF2 transcription factor controls a cell stress program that is implicated in cancer. Role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer. The development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo, role of FN3K-sensitive NRF2 glycation in liver cancer in vivo, overview	760823	
2.7.1.171	physiological function	fructosamine-3-kinase (FN3K) is involved in deglycation, active in removing ketoamines, and preventing advanced glycation end product production. Enzyme FN3K is capable of counteracting the effect of hyperglycemia by intervening in protein glycation. The FN3K genetic variability is linked to the enzyme's enzymatic activity and glycated hemoglobin (HbA1c) levels	760800	
2.7.1.171	physiological function	fructosamine-3-kinase (FN3K) is involved in natural cellular repair mechanisms to control non-enzymatic glycation of proteins. It also has potential in the disruption of retinal advanced glycation end products (AGEs), which are important risk factor in pathogenesis in complement, lipid, angiogenic, inflammatory and extracellular matrix pathways in the eye. Increased levels of AGEs have been found in the Bruch's membrane, retinal pigment epithelium (RPE) and drusen of patients with age-related macular degeneration (AMD), a degenerative disorder of the macular region of the retina. Analysis of FN3K treatment of AGE-modified neural porcine, murine, and human retinas. The treatment reduces AGE-related autofluorescence. Murine and human eyes treated intravitreally with FN3K show less drusenoid material and lesions on stained tissue sections. Biochemical changes after FN3K treatment, overview. Near-infrared (NIR) microspectroscopy of the Bruch's membrane and drusen on hematoxylin and eosin stained slides originating from two patients with stage 3 age-related macular degeneration (AMD). Vivo intravitreal FN3K treatment on human eyes strongly reduces size of subretinal drusenoid deposits on optical coherence tomography	761600	
2.7.1.171	physiological function	impact on glycation, and possibly on diabetic complications, is attributed to fructosamine-3-kinase (FN3K) and its related protein (FN3K-RP) because they degrade Amadori compounds in vivo. Individual differences in FN3K-RP activity might contribute to an individual risk for diabetic complications	738072	
2.7.1.171	physiological function	the physiological function of fructosamine-3-kinase may be to initiate a process leading to the deglycation of fructoselysine and of glycated proteins	708294	
2.7.1.171	physiological function	variations in the level of the deglycating enzyme fructosamine-3-kinase (FN3K) might be associated with the glycation gap (GGap), a phenomenon of a discrepancy between glycated hemoglobin levels and other indicators of average glycemia may be due to many factors. GGap is associated with differences in complications in patients with diabetes and may possibly be explained by dissimilarities in deglycation in turn leading to altered production of advanced glycation end products (AGEs). Increased erythrocyte FN3K concentrations and enzyme activity (323%) are determined in a population dichotomized for a large positive or negative GGap. This is associated with lower AGE levels in the negative-GGap group (79%), lower proinflammatory adipokines (leptin-to-adiponectin ratio) (73%), and much lower prothrombotic PAI-1 levels (19%). FN3K may play a key role in the GGap and thus diabetes complications	760954