33 results on '"deglycation"'
Search Results
2. Fructosamine 3-Kinase in Erythrocytes for Myocardial Infarction Patients.
- Author
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Mohammed, Rafad R. S. and Abdulrahman, Tamara Sh.
- Subjects
- *
OXIDANT status , *MYOCARDIAL infarction , *GLYCOSYLATED hemoglobin , *BLOOD sugar , *OXIDATIVE stress - Abstract
Background: Fructosamine-3-kinase (FN3K) enzyme appears to protect proteins from nonenzymatic glycation. Objectives: The current study aimed to establish the activity of FN3K in serum and erythrocyte lysate. Methods: The activity of FN3K were estimated in (30) healthy individuals and compared to values in (35) non-diabetic myocardial infarction patients. Results: The results showed that there was a significant increase in the activity of enzymes in the lysate of erythrocytes, compared with the activity of enzymes in serum for both the control groups and the patients group. The results also showed a significant increase in the activity of the FN3K enzyme in the serum of patients compared to the control group. The activity of enzymes is not affected by gender for both groups. A group of biochemical variables related to myocardial infarction were measured. The result showed a negative significant relationship between the activity of the enzyme and the level of total antioxidant capacity a positive significance in glycated hemoglobin in the control group, and patients positive significance between the activity of the enzyme and the level of Zn. Conclusion: The activity of FN3K enzyme is affected by age, uncontrol blood glucose levels, and oxidative stress in healthy patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
3. Synthesis and antiglycation activity of 3‐phenacyl substituted thiazolium salts, new analogs of Alagebrium.
- Author
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Ozerov, Alexander, Merezhkina, Darya, Zubkov, Fedor I., Litvinov, Roman, Ibragimova, Umida, Valuisky, Nikita, Borisov, Alexander, and Spasov, Alexander
- Subjects
- *
ANTIGLYCATION agents , *AB-initio calculations , *SALTS , *PYRUVALDEHYDE - Abstract
After preliminary ab initio calculations, 3‐phenacyl substituted thiazolium salts, analogs of Alagebrium, were synthesized and investigated in vitro as glycation reaction inhibitors. The most part of investigations focused on the potential of the title compounds to attenuate the formation of fluorescent AGEs as well on their ability to disrupt the cross‐linking formation among glycated proteins. Additionally, the capability of thiazolium salts to deglycate in the reaction of early glycation products with nitroblue tetrazolium was determined. Cytotoxicological properties of the title compounds were evaluated using LDH and MTT assays. The leader compound (3‐[2‐(biphenyl‐4‐yl)‐2‐oxoethyl]‐1,3‐thiazol‐3‐ium bromide) in a 50 mg/kg dose (p.o. 14 days) was further tested within an in vivo carbonyl stress model (rats, methylglyoxal 86.25 mg/kg/d, i.p., 14 days). As a result, the leader‐molecule revealed a high effectiveness against all three examined mechanisms of glycation reaction inhibition in in vitro tests and was able to suppress capacity of methylglyoxal to form AGEs in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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4. Novel regulators of mitochondrial genome integrity.
- Author
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Nair, Ashwin and Shivaprasad, P V
- Abstract
Mitochondrial genomes are unusual in that they have very low mutation rates in coding sequences when compared with animals, yeast, and bacteria. It has been proposed that the mitochondrial (mt) DNA damage is preferentially repaired by homologous recombination (HR). In this short review, we summarize and discuss the well-established and recently identified pathways that help in maintaining the integrity of plant mitochondrial genomes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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5. Lipoprotein Glycation in Diabetes Mellitus
- Author
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Jenkins, Alicia J., Klein, Richard L., Semler, Andrea J., Januszewski, Andrzej S., Veves, Aristidis, Series Editor, Jenkins, Alicia J., editor, and Toth, Peter P., editor
- Published
- 2023
- Full Text
- View/download PDF
6. Assessment of Fructosamine 3-kinase in Type 2 Diabetic Patients and Its Relation to Some Biochemical Variables.
- Author
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Abdulrahman, Tamara Sh. and Mohammed, Rafad R. S.
- Subjects
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KINASES , *TYPE 2 diabetes , *MAMMALS , *AGE groups , *VITAMIN C - Abstract
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]
- Published
- 2023
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7. Comparative biological evaluation and identification of multifunctional endogenous and exogenous bioactive peptides in different matured Izmir Tulum cheeses.
- Author
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Akan, Ecem, Tok, Kerem, Kocazorbaz, Ebru Kocadag, Zihnioglu, Figen, Yerlikaya, Oktay, Hayaloglu, Ali Adnan, and Kinik, Ozer
- Subjects
- *
DIETARY bioactive peptides , *AMINO acid sequence , *CHEESEMAKING , *PEPTIDES , *TYPE 2 diabetes , *GOAT milk - Abstract
Bioactive peptides redefine health and disease by triggering unique biological functions in the body. The aim of this study was to evaluate and identify the endogenous and exogenous peptides (in vitro gastrointestinal digestion) of 360-day ripened Izmir Tulum cheese manufactured using cow, sheep, and goat milk. Peptide extracts from Izmir Tulum cheeses were found to have DPP-IV inhibitory, deglycation, antioxidant, metal chelating, and ACE-inhibitory activity. After the activity guided purification of peptide extracts were performed by HPLC, 8 peptide fractions were selected according to their biological activity, and the peptide sequence of each peptide were identified by mass spectrometry. It was observed that the use of different types of milk in the manufacture of Izmir Tulum cheese affects peptide diversity, that endogenous and exogenous peptides had a wide range of potential biological activities, and that new bioactive peptides were obtained from Izmir Tulum cheese. The potential peptide sequences obtained from the identified fractions ETFHPLKHQ, EVVPGPFPQ, and TLGLHTPK are the first peptide sequences that do not overlap with sequences published in the literature. In conclusion, these endogenous and exogenous peptides of Izmir Tulum cheeses have significant biological activities associated with type 2 diabetes, deglycation, antioxidants, and metal chelating agents to support the immune system, and ACE-inhibitory effects to treat hypertension. These new peptides could open a new avenue for the noval peptide-based drug and contribute to therapeutic applications. [ABSTRACT FROM AUTHOR]
- Published
- 2025
- Full Text
- View/download PDF
8. The role of a deglycating enzyme 'fructosamine-3-kinase' in diabetes and COPD
- Author
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Alderawi, Amr Saleh
- Subjects
616.07 ,Advanced Glycation End products ,COPD ,CVDs ,Diabetes ,Deglycation ,Fructosamine-3-kinase ,Glycated Haemoglobin ,Glycation Gap ,Metformin & Smoking - Abstract
Recent statistics show that approximately 415 million people worldwide have diabetes. Glycated haemoglobin (HbA1c) measurements were introduced many years ago as the gold standard tool for detecting and monitoring treatment as well as making management decisions for diabetic patients. Glycated haemoglobins are formed by the non-enzymatic glycation of haemoglobin molecules. This non-enzymatic glycation process has been strongly related to pathogenesis of chronic complications associated to diabetes. It was suggested that this glycation process may be moderated by an enzymatic deglycation process thought to involve a deglycating enzyme known as Fructosamine-3-kinase (FN3K), an enzyme that deglycates the glycated haemoglobin in erythrocytes and other glycated proteins in other tissues. FN3K acts through phosphorylation of fructosamines on the third carbon of their sugar moiety, making them unstable and consequently causing them to detach from the protein. The degree of deglycation is thought to depend on the activity of the FN3K enzyme. Moreover, variation in the activity of FN3K between individuals is hypothesised to lead to apparent differences in glycated haemoglobin levels: some individuals have high rates of deglycation so that they tend to have lower average glycaemia than actually the case, while others with low rates of deglycation appear to have higher than actual glycaemia (known as the glycation gap, G-gap). The G-gap has been reported to be associated with alteration of diabetic complications risk. The G-gap reflects the discrepancy between average glycaemia as determined from glycated haemoglobin (measured as HbA1c) and that from the determination of fructosamine. The positive G-gap is defined as a higher level of glycation of proteins than expected whereas a negative G-gap means a lower level of glycation than expected. To explore the role of FN3K in diabetes and other associated morbidities, we decided to divide our research into 3 studies. Each study was categorised according to the type and the source of samples involved. The first study explored the correlation between FN3K activity and protein level with G-gap data; it involved 148 diabetic patients who were recruited at New Cross Hospital, Wolverhampton, selected as having a consistent positive G-gap > +0.5 and a consistent negative G-gap > -0.5 over a minimum of 2 estimations. Age, gender, race and BMI were collected from patients in this study. Blood samples were also 3 collected to measure FN3K activity, protein levels, and markers of CVD in relation to G-gap. The second study involved 23 AECOPD patients who were recruited from St George’s Hospital (London) and were treated with either metformin or a placebo. Serum samples were collected from these patients for a larger study: we assayed those 23 serum samples for FN3K protein levels to explore any possible correlation between FN3K with metformin therapy in COPD patients. The third study utilised 36 human peripheral lung samples from healthy individuals, asymptomatic smokers and stable COPD patients (GOLD 2) who were recruited at The Section of Respiratory Medicine, University Hospital of Ferrara, Italy. Those samples were assessed for FN3K expression by means of immunohistochemistry to explore the difference in FN3K activity between those three categories. It was found that the intracellular activity and protein expression of the FN3K enzyme in diabetic patients negatively correlated with the values of G-gaps where FN3K activity was high in patients with negative G-gap. FN3K serum protein levels were shown to be enhanced with metformin administration in COPD diabetic patients, suggesting a protective role for FN3K enzyme against protein damaged caused by the non-enzymatic glycation of proteins. Therefore, patients with positive G-gap have lower FN3K activity than those with negative G-gap, and in turn they are more susceptible to diabetes related complications. Our data also indicate that metformin has a beneficial effect in reducing damage caused by carbonyl stress from cigarette smoking in COPD patients by the action of FN3K. Our research has demonstrated that FN3K contributes to the protein repair system which protects against damage caused by non-enzymatic glycation. The high activity for the FN3K enzyme was associated with low levels of AGEs and low carbonyl stress levels in observed among patients with diabetes and COPD. In contrast, COPD patients tend to have low FN3K-mediated protection against protein damage in comparison to the normal population. These patients tend to be at risk for developing more complications, particularly CVD complications, than normal, healthy individuals. Treatment with metformin enhances FN3K action in COPD diabetic patients, possibly as a protective enzyme against the damaged caused by the non-enzymatic glycation.
- Published
- 2017
9. A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines.
- Author
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Szwergold, Benjamin and Szwergold, Benjamin S
- Subjects
- *
BIOMACROMOLECULES , *MAILLARD reaction , *FOOD chemistry , *FREE radicals , *DEFENSE reaction (Physiology) - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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10. Metabolization of the Amadori Product N -ε-Fructosyllysine by Probiotic Bacteria.
- Author
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Filipp L, Bausch F, Neuhaus LS, Flade J, and Henle T
- Subjects
- Lysine metabolism, Bacteria metabolism, Sugars, Lactic Acid, Lactobacillales metabolism, Probiotics
- Abstract
Glycation reactions in food lead to the formation of the Amadori rearrangement product (ARP) N -ε-fructosyllysine (fructoselysine, FL), which is taken up with the daily diet and comes into contact with the gut microbiota during digestion. In the present study, nine commercially available probiotic preparations as well as single pure strains thereof were investigated for their FL-degrading capability under anaerobic conditions. One of the commercial preparations as well as three single pure strains thereof was able to completely degrade 0.25 mM FL within 72 h. Three new deglycating lactic acid bacteria species, namely, Lactobacillus buchneri DSM 20057, Lactobacillus jensenii DSM 20557, and Pediococcus acidilactici DSM 25404, could be identified. Quantitative experiments showed that FL was completely deglycated to lysine. Using
13 C6 -labeled FL as the substrate, it could be proven that the sugar moiety of the Amadori product is degraded to lactic acid, showing for the first time that certain lactic acid bacteria can utilize the sugar moiety as a substrate for lactic acid fermentation.- Published
- 2024
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11. A method to quantify intracellular glycation in dermal fibroblasts using liquid chromatography coupled to fluorescence detection – Application to the selection of deglycation compounds of dermatological interest.
- Author
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André, Amandine, Wdzieczak-Bakala, Joanna, Touré, Alexis Kaatio, Stien, Didier, and Eparvier, Véronique
- Subjects
- *
LIQUID chromatography , *FLUORESCENCE , *DERMATOLOGY , *PEOPLE with diabetes , *ADVANCED glycation end-products , *FIBROBLASTS - Abstract
Abstract Glycation is a common non-enzymatic reaction between proteins and sugars, which gives rise in the human body to the formation of advanced glycation end products (AGEs). These modifications impacts both extra and intracellular proteins, leading to cells and tissues dysfunctions. In the skin, accumulation of AGEs leads to aesthetic consequences, wrinkles, dark spots and yellowish skin tone, as it can be seen in diabetic patients. Consequently, there is a growing dermatological interest to find compounds able to eliminate AGEs accumulated in skin. In this context, a method has been developed to detect and quantify intracellular glycation in human dermal fibroblasts. After cultivation of fibroblasts, cell lysates were injected in an HPLC system coupled with a fluorescence detector in by-pass mode. The system allows the simultaneous measurement of global AGEs and particular pentosidine amounts using two sets of wavelengths in a single run of 1 min. The immunocytochemistry approach was used to valid the HPLC analysis data. The method developed was able to quantify changes in global AGEs and pentosidine content in cells in response to glyoxal treatment. Fibroblasts treated with 500 μM of glyoxal for 48 h showed a significant 2.3-fold and 2.6-fold increase in the content of AGEs and pentosidine respectively compared to control cells. As an application, a screening of natural extracts have been done and the method allowed identifying extracts able to significantly reduce the amount of pentosidine in fibroblasts (−32%). These extracts act as deglycation agents of interest in the field of dermatology and cosmetology. Highlights • HPLC-Fluorescence based method to detect and quantify Advanced Glycation End products (AGEs) in cells • The method is suitable to detect multiple glycation compounds in the same run. • The ability of natural extracts to reduce the intracellular level of AGEs can be rapidly determined. • The method can be applied to discover new deglycation active compounds of dermatological and cosmetological interest. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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12. Optimizing glycation control in diabetes: An integrated approach for inhibiting nonenzymatic glycation reactions of biological macromolecules.
- Author
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Song, Hongwei, Ma, Hongyan, Shi, Junfeng, Liu, Yongping, Kan, Chengxia, Hou, Ningning, Han, Jing, Sun, Xiaodong, and Qiu, Hongyan
- Subjects
- *
BIOMACROMOLECULES , *ADVANCED glycation end-products , *RECEPTOR for advanced glycation end products (RAGE) , *BLOOD sugar , *DIABETES complications , *PARKINSON'S disease - Abstract
Diabetes is a multifactorial disorder that increases mortality and disability due to its complications. A key driver of these complications is nonenzymatic glycation, which generates advanced glycation end-products (AGEs) that impair tissue function. Therefore, effective nonenzymatic glycation prevention and control strategies are urgently needed. This review comprehensively describes the molecular mechanisms and pathological consequences of nonenzymatic glycation in diabetes and outlines various anti-glycation strategies, such as lowering plasma glucose, interfering with the glycation reaction, and degrading early and late glycation products. Diet, exercise, and hypoglycemic medications can reduce the onset of high glucose at the source. Glucose or amino acid analogs such as flavonoids, lysine and aminoguanidine competitively bind to proteins or glucose to block the initial nonenzymatic glycation reaction. In addition, deglycation enzymes such as amadoriase, fructosamine-3-kinase, parkinson's disease protein, glutamine amidotransferase-like class 1 domain-containing 3A and terminal FraB deglycase can eliminate existing nonenzymatic glycation products. These strategies involve nutritional, pharmacological, and enzymatic interventions that target different stages of nonenzymatic glycation. This review also emphasizes the therapeutic potential of anti-glycation drugs for preventing and treating diabetes complications. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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13. Possible role of fructosamine 3-kinase genotyping for the management of diabetic patients.
- Author
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Avemaria, Francesca, Carrera, Paola, Lapolla, Annunziata, Sartore, Giovanni, Chilelli, Nino Cristiano, Paleari, Renata, Ambrosi, Alessandro, Ferrari, Maurizio, and Mosca, Andrea
- Abstract
Diabetes mellitus is a global pandemic and continues to increase in numbers and significance. Several pathogenic processes are involved in the development of such disease and these mechanisms could be influenced by genetic, epigenetic and environmental factors. Non-enzymatic glycation reactions of proteins have been strongly related to pathogenesis of chronic diabetic complications. The identification of fructosamine 3-kinase (FN3K), an enzyme involved in protein deglycation, a new form of protein repair, is of great interest. 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. Moreover, the variability in FN3K activity has been associated with some polymorphisms in the FN3K gene. Here we argue about genetic studies and evidence of FN3K involvement in diabetes, together with results of our analysis of the FN3K gene on a Caucasian cohort of diabetic patients. Present knowledge suggests that FN3K could act in concert with other molecular mechanisms and may impact on gene expression and activity of other enzymes involved in deglycation process. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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14. The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers
- Author
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Asha Srinivasan, SubbaRao V. Madhunapantula, Shalini H Doreswamy, Narasimha M Beeraka, Venugopal R. Bovilla, and Sujatha Puttalingaiah
- Subjects
0301 basic medicine ,deglycation ,Cancer Research ,Angiogenesis ,Review ,medicine.disease_cause ,environment and public health ,AGEs ,lcsh:RC254-282 ,Nrf2 ,RAGE (receptor) ,03 medical and health sciences ,0302 clinical medicine ,Glycation ,medicine ,Protein kinase A ,Chemistry ,respiratory system ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RAGE ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,glycation ,Tumor necrosis factor alpha ,Signal transduction ,FN3K ,Carcinogenesis - Abstract
Simple Summary Aim of this review is to provide an overview on (a) Fructosamine-3-Kinase (FN3K) and its role in regulating Nuclear Factor Erythorid-2-Related Factor-2 (Nrf2); (b) the role of glycation and deglycation mechanisms in modulating the functional properties of proteins, in particular, the Nrf2; (c) the dual role of Nrf2 in the prevention and treatment of cancers. Since controlling the glycation of Nrf2 is one of the key mechanisms determining the fate of a cell; whether to get transformed into a cancerous one or to stay as a normal one, it is important to regulate Nrf2 and deglycating FN3K using pharmacological agents. Inhibitors of FN3K are being explored currently to modulate Nrf2 activity thereby control the cancers. Abstract Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.
- Published
- 2021
15. A potential role for fructosamine-3-kinase in cataract treatment
- Author
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Nezahat Bostan, Marijn M. Speeckaert, Wim Derave, Inge Everaert, Jonas Himpe, Filip De Somer, Nico Callewaert, Sander De Bruyne, Elisabeth Van Aken, Manon Huizing, Joris R. Delanghe, Caroline Van den Broecke, and Loes van Schie
- Subjects
0301 basic medicine ,Glycation End Products, Advanced ,genetic structures ,medicine.medical_treatment ,Eye ,law.invention ,lcsh:Chemistry ,Lens protein ,Mice ,0302 clinical medicine ,law ,Glycation ,Medicine and Health Sciences ,therapeutics ,lcsh:QH301-705.5 ,Saline ,fructosamine-3-kinase ,Spectroscopy ,Chemistry ,advanced glycation end products ,General Medicine ,Immunohistochemistry ,Computer Science Applications ,Lens (optics) ,Phosphotransferases (Alcohol Group Acceptor) ,cataract ,Intravitreal Injections ,deglycation ,medicine.medical_specialty ,Article ,Cataract ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Cataracts ,In vivo ,Crystallin ,Ophthalmology ,Lens, Crystalline ,medicine ,Animals ,Humans ,Horses ,Physical and Theoretical Chemistry ,Biology ,Molecular Biology ,Dose-Response Relationship, Drug ,Organic Chemistry ,Biology and Life Sciences ,medicine.disease ,eye diseases ,Enzyme Activation ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,030221 ophthalmology & optometry ,sense organs ,Ex vivo - Abstract
Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNF alpha, and IFN gamma using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts.
- Published
- 2021
16. THE EPIDEMIOLOGY AND BURDEN OF CARDIOMETABOLIC RISK FACTORS IN A YOUNG EMIRATI POPULATION
- Author
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Luai A. Ahmed, Rami H. Al-Rifai, Mezhal, Fatima Abobakr Hussein, Luai A. Ahmed, Rami H. Al-Rifai, and Mezhal, Fatima Abobakr Hussein
- Abstract
The United Arab Emirates (UAE) has experienced rapid economic growth that was paralleled by a drastic rise in non-communicable diseases (NCDs); primarily cardiovascular diseases (CVDs), which account for 40% of mortality in UAE. CVDs have complex etiology, interplay, and accumulation of many risk factors. Understanding the clustering and interrelationships between common risk factors like obesity, deglycation, dyslipidemia, hypertension and central obesity, and the associations with social and lifestyle determinants are warranted. The study aimed to estimate the burden of cardiometabolic risk factors (CRFs), their interrelationship, and their associations with other social and lifestyle determinants in a young Emirati population. Data were drawn from the UAE Healthy Future Study collected between 2016 and 2018. The information was collected through questionnaires, physical measurements, and blood samples. Age-adjusted and gender-specific prevalence of CRFs were estimated, and appropriate regression models were used to determine the interrelationships and associations of the CRFs. A total of 5,167 eligible participants aged 18-40 were included in the analysis. The age-adjusted prevalence rates were 26.5% for obesity, 11.7% for deglycation, 62.7% for dyslipidemia, 22.4% for hypertension and 22.5% for central obesity. Dyslipidemia had the highest comorbidity rate, up to 80%, with other CRFs, followed by obesity. Obesity had the strongest interrelationship with other CRFs. Education, employment, smoking and family history of NCDs had significant associations with some CRFs. Forty per cent of the population had ≥2 CRFs, and the accumulation was higher in men than women; 47.8% vs 28.1%, respectively. The burden of CRFs was affected by age and social factors and was significantly different across BMI classes. CRFs and their clustering are highly prevalent in young adults, including those with normal BMI. This should be considered in the design and targeting of group-spe
- Published
- 2020
17. Enzymatic repair of Amadori products.
- Author
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Schaftingen, Emile, Collard, François, Wiame, Elsa, and Veiga-da-Cunha, Maria
- Subjects
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AMADORI compounds , *FRUCTOSAMINE , *PHOSPHORYLATION , *PROTEIN-protein interactions , *MOLECULAR weights , *BLOOD cells , *ENZYME analysis , *LABORATORY mice - Abstract
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]
- Published
- 2012
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18. Enzymatic deglycation of Amadori products in bacteria: mechanisms, occurrence and physiological functions.
- Author
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Deppe, Veronika Maria, Bongaerts, Johannes, O'Connell, Timothy, Maurer, Karl-Heinz, and Meinhardt, Friedhelm
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- *
ENZYME kinetics , *BACILLUS subtilis , *ESCHERICHIA coli biotechnology , *GENETIC transformation , *BIODEGRADATION , *ATP-binding cassette transporters - Abstract
madori products (fructosamines)-ubiquitously occurring in nature-are precursors of the toxic and cell damaging 'advanced glycation endproducts'; thus, it is not surprising that numerous organisms have developed systems to degrade such compounds. The deglycating enzymes differ with respect to their mechanisms as well as to their substrate specificities. Furthermore, different physiological functions are proposed for the different enzymes. The fructosamine 3-kinases of mammals and homologous proteins (fructosamine 3-kinase related proteins), which are common to all taxa, are thought to focus on intracellular repair functions. In contrast, in Bacillus subtilis and Escherichia coli, the cooperative action of a kinase and a deglycase facilitates Amadori degradation. As genes encoding these enzymes are co-transcribed with ABC transporter genes, it is thought that these genes facilitate the utilisation of extracellular Amadori products. Indeed, it has been shown that fructosamines can serve as the sole carbon and nitrogen sources. Here, we provide an overview of known deglycating systems with the emphasis on Amadori product degradation in bacteria. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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19. Fructosamine-3-kinase-related-protein phosphorylates glucitolamines on the C-4 hydroxyl: Novel substrate specificity of an enigmatic enzyme
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Szwergold, Benjamin, Manevich, Yefim, Payne, Leo, and Loomes, Kerry
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- *
FOCAL adhesion kinase , *CYTOSKELETAL proteins , *PROTEIN-tyrosine kinases , *MEDICAL sciences - Abstract
Abstract: Fructosamine-3-kinase (FN3K) phosphorylates fructosamines to fructosamine-3-phosphates. Recent data from FN3K-knockout mouse indicate that this phosphorylation results in deglycation of proteins modified by non-enzymatic glycation process. A homolog of FN3K, the FN3K-related-protein (FN3KRP) displays 65% amino acid sequence identity with FN3K and is highly conserved in evolution. However, FN3KRP does not phosphorylate substrates of FN3K such as fructoselysine and its physiological function remains unknown. We observed that human erythrocytes that contain both enzymes phosphorylate N-methylglucamine (meglumine) to two products. One of these is meglumine-3-phosphate (Meg3P), an activity consistent with the known substrate specificity of FN3K. Here, we identify the second product as meglumine-4-phosphate (Meg4P) and show that it is produced specifically by FN3KRP. While it is unlikely that meglumine is the physiological target of FN3KRP, this novel specificity, along with FN3KRPs known phosphorylation of some ketosamines on the C-3 hydroxyl may prove useful in identifying the physiological substrates of this kinase. [Copyright &y& Elsevier]
- Published
- 2007
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20. Many fructosamine 3-kinase homologues in bacteria are ribulosamine/erythrulosamine 3-kinases potentially involved in protein deglycation.
- Author
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Gemayel, Rita, Fortpied, Juliette, Rzem, Rim, Vertommen, Didier, Veiga-da-Cunha, Maria, and Van Schaftingen, Emile
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- *
FUNGUS-bacterium relationships , *GENOMICS , *LACTOBACILLUS , *STAPHYLOCOCCUS aureus , *STAPHYLOCOCCUS aureus infections , *GENOMES - Abstract
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]
- Published
- 2007
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21. Identification of 3-deoxyglucosone dehydrogenase as aldehyde dehydrogenase 1A1 (retinaldehyde dehydrogenase 1)
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Collard, François, Vertommen, Didier, Fortpied, Juliette, Duester, Gregg, and Van Schaftingen, Emile
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- *
DEHYDROGENASES , *ORGANS (Anatomy) , *PRESERVATION of organs, tissues, etc. , *TISSUES - Abstract
Abstract: One of the metabolic fates of 3-deoxyglucosone, a product of protein deglycation and a potent glycating agent, is to be oxidized to 2-keto-3-deoxygluconate, but the enzyme that catalyzes this reaction is presently unknown. Starting from human erythrocytes, which are known to convert 3-deoxyglucosone to 2-keto-3-deoxygluconate, we have purified to near homogeneity a NAD-dependent dehydrogenase that catalyzes this last reaction at neutral pH. Sequencing of a 55kDa band co-eluting with the enzymatic activity in the last step indicated that it corresponded to aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme known to catalyze the oxidation of retinaldehyde to retinoic acid. Overexpression of human ALDH1A1 in HEK cells led to a more than 20-fold increase in 3-deoxyglucosone dehydrogenase activity. In mouse tissues 3-deoxyglucosone dehydrogenase activity was highest in liver, intermediate in lung and testis, and negligible or undetectable in other tissues, in agreement with the tissue distribution of ALDH1A1 mRNA. 3-Deoxyglucosone dehydrogenase activity was undetectable in tissues from ALDH1A1−/− mice. ALDH1A1 appears therefore to be the major if not the only enzyme responsible for the oxidation of 3-deoxyglucosone to 2-keto-3-deoxygluconate. The urinary excretion of 2-keto-3-deoxygluconate amounted to 16.7μmol/g creatinine in humans, indicating that 3-deoxyglucosone may be quantitatively a more important substrate than retinaldehyde for ALDH1A1. [Copyright &y& Elsevier]
- Published
- 2007
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22. Variability in erythrocyte fructosamine 3-kinase activity in humans correlates with polymorphisms in the FN3K gene and impacts on haemoglobin glycation at specific sites.
- Author
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Delpierre, G, Veiga-da-Cunha, M, Vertommen, D, Buysschaert, M, and Van Schaftingen, E
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ERYTHROCYTES ,HEMOGLOBINS ,BLOOD sugar ,HYPERGLYCEMIA ,DIABETES complications - Abstract
Copyright of Diabetes & Metabolism is the property of Masson Editeur and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2006
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23. Carnosine and anserine act as effective transglycating agents in decomposition of aldose-derived Schiff bases
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Szwergold, Benjamin S.
- Subjects
- *
CARNOSINE , *PROTEINS , *PEPTIDES , *AMINO acids - Abstract
Abstract: There are numerous publications describing the positive effects of carnosine (β-alanyl-histidine) and anserine (β-alanyl-1-N-methyl-histidine) on cell and organ function. Of special interest to us is the fact that these dipeptides act to retard and (in one instance) reverse non-enzymatic glycation. To date, the primary explanation for these anti-glycating effects has been the fact that carnosine and anserine can serve as alternative and competitive glycation targets, thereby protecting proteins from this deleterious process. In this paper, we document another mechanism by which these two peptides can retard or reverse glycation. The process involves decomposition of the very first intermediates of the non-enzymatic glycation cascade (aldosamines a.k.a. Schiff bases) by nucleophilic attack of carnosine and/or anserine on the preformed aldosamine such as glucosyl-lysine. If future research shows this reaction is to be physiologically important, this mechanism could explain some of the beneficial effects of carnosine and anserine as anti-glycating agents. [Copyright &y& Elsevier]
- Published
- 2005
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24. Some Clues as to the Regulation, Expression, Function, and Distribution of Fructosamine-3-Kinase and Fructosamine-3-Kinase--Related Protein.
- Author
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CONNER, JAMES R., BEISSWENGER, PAUL J., and SZWERGOLD, BENJAMIN S.
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POLYMERASE chain reaction ,HYPERGLYCEMIA ,BLOOD sugar ,INTERLEUKIN-1 ,MESSENGER RNA - Abstract
Fructosamine-3-kinase (FN3K) and the more recently discovered fructosamine-3-kinase-related protein (FN3KRP) appear to protect proteins from nonenzymatic glycation. To gain a better understanding of these enzymes we performed a series of investigations including (1) in silico comparisons of their promoters; (2) real-time PCR analysis of their expression in human tissues; (3) effects of hyperglycemia, interleukin-1β (IL-1β), and nuclear factor kappa-B (NFκB) activation on their mRNA levels; (4) effects of small interfering RNA (siRNA) suppression of FN3K expression (knockdown) in cultured cells and (5) search of FN3K and FN3KRP homologs in available genomic and EST (expressed sequence tag) databases. 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. (2) Both genes are expressed in all human tissue examined, with FN3K showing significantly higher levels in tissues susceptible to nonenzymatic glycation and diabetic complications. (3) Treatment of fibroblasts with high glucose, IL-1β, and activation of NFκB does not affect the expression of either FN3K or FN3KRP. (4) Knockdown of FN3K in cultured cells inhibits or arrests their growth. (5) FN3K-like genes are widely distributed in nature, with the notable exception of insects and yeasts. These data suggest that FN3K and FN3KRP are constitutive "housekeeping" genes and that they play an important role in cell metabolism, possibly as deglycating enzymes. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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25. The expression of the genes for fructosamine-3-kinase and fructosamine-3-kinase-related protein appears to be constitutive and unaffected by environmental signals
- Author
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Conner, James R., Beisswenger, Paul J., and Szwergold, Benjamin S.
- Subjects
- *
GENE expression , *PROTEINS , *TISSUES , *FIBROBLASTS - Abstract
Fructosamine-3-kinase (FN3K) and the more recently discovered fructosamine-3-kinase related protein (FN3KRP) appear to protect proteins from nonenzymatic glycation. To elucidate the patterns of transcriptional regulation of these two genes, we performed in silico comparisons of their promoters along with real-time PCR assays of their expression in a variety of human tissues. Both promoters were TATA-less and CAAT-less, and contained several homologous CpG islands and Sp1 binding sites. The genes were expressed in all human tissues examined, with FN3K showing significantly higher levels in organs susceptible to nonenzymatic glycation and diabetic complications. 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. 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. [Copyright &y& Elsevier]
- Published
- 2004
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26. A method to quantify intracellular glycation in dermal fibroblasts using liquid chromatography coupled to fluorescence detection – Application to the selection of deglycation compounds of dermatological interest
- Author
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Didier Stien, Alexis Kaatio Touré, Joanna Wdzieczak-Bakala, Véronique Eparvier, Amandine André, Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire Shigeta, Laboratoire de Biodiversité et Biotechnologies Microbiennes (LBBM), PIERRE FABRE-EDF (EDF)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Observatoire océanologique de Banyuls (OOB), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Cell Extracts ,Glycation End Products, Advanced ,Glycosylation ,Clinical Biochemistry ,Immunocytochemistry ,Context (language use) ,Biochemistry ,High-performance liquid chromatography ,Fluorescence spectroscopy ,Fluorescence ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Advanced glycation end product (AGEs) ,Glycation ,Humans ,[CHIM]Chemical Sciences ,Pentosidine ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Human dermal fibroblasts ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Skin ,Chromatography ,Reproducibility of Results ,Cell Biology ,General Medicine ,Fibroblasts ,Middle Aged ,030104 developmental biology ,chemistry ,Microscopy, Fluorescence ,030220 oncology & carcinogenesis ,Glyoxal ,Female ,Deglycation ,HPLC ,Intracellular ,Chromatography, Liquid - Abstract
International audience; Glycation is a common non-enzymatic reaction between proteins and sugars, which gives rise in the human body to the formation of advanced glycation end products (AGEs). These modifications impacts both extra and intracellular proteins, leading to cells and tissues dysfunctions. In the skin, accumulation of AGEs leads to aesthetic consequences, wrinkles, dark spots and yellowish skin tone, as it can be seen in diabetic patients. Consequently, there is a growing dermatological interest to find compounds able to eliminate AGEs accumulated in skin.In this context, a method has been developed to detect and quantify intracellular glycation in human dermal fibroblasts. After cultivation of fibroblasts, cell lysates were injected in an HPLC system coupled with a fluorescence detector in by-pass mode. The system allows the simultaneous measurement of global AGEs and particular pentosidine amounts using two sets of wavelengths in a single run of 1 min. The immunocytochemistry approach was used to valid the HPLC analysis data.The method developed was able to quantify changes in global AGEs and pentosidine content in cells in response to glyoxal treatment. Fibroblasts treated with 500 μM of glyoxal for 48 h showed a significant 2.3-fold and 2.6-fold increase in the content of AGEs and pentosidine respectively compared to control cells.As an application, a screening of natural extracts have been done and the method allowed identifying extracts able to significantly reduce the amount of pentosidine in fibroblasts (−32%). These extracts act as deglycation agents of interest in the field of dermatology and cosmetology.
- Published
- 2018
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27. A Potential Role for Fructosamine-3-Kinase in Cataract Treatment.
- Author
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De Bruyne, Sander, van Schie, Loes, Himpe, Jonas, De Somer, Filip, Everaert, Inge, Derave, Wim, Van den Broecke, Caroline, Huizing, Manon, Bostan, Nezahat, Speeckaert, Marijn, Callewaert, Nico, Van Aken, Elisabeth, and Delanghe, Joris R.
- Subjects
- *
RECEPTOR for advanced glycation end products (RAGE) , *ADVANCED glycation end-products , *CRYSTALLINE lens , *INTRAVITREAL injections , *CATARACT - Abstract
Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNFα, and IFNγ using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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28. The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers.
- Author
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Beeraka, Narasimha M., Bovilla, Venugopal R., Doreswamy, Shalini H., Puttalingaiah, Sujatha, Srinivasan, Asha, and Madhunapantula, SubbaRao V.
- Subjects
- *
ANTINEOPLASTIC agents , *ANTIOXIDANTS , *CARBOHYDRATES , *CELLULAR signal transduction , *GLYCOSYLATION , *PHOSPHORYLATION , *PROTEIN kinases , *TRANSCRIPTION factors , *TUMORS , *OXIDATIVE stress , *PROTEIN kinase inhibitors , *NEOPLASTIC cell transformation , *CHEMICAL inhibitors , *PHARMACODYNAMICS ,TUMOR prevention - Abstract
Simple Summary: Aim of this review is to provide an overview on (a) Fructosamine-3-Kinase (FN3K) and its role in regulating Nuclear Factor Erythorid-2-Related Factor-2 (Nrf2); (b) the role of glycation and deglycation mechanisms in modulating the functional properties of proteins, in particular, the Nrf2; (c) the dual role of Nrf2 in the prevention and treatment of cancers. Since controlling the glycation of Nrf2 is one of the key mechanisms determining the fate of a cell; whether to get transformed into a cancerous one or to stay as a normal one, it is important to regulate Nrf2 and deglycating FN3K using pharmacological agents. Inhibitors of FN3K are being explored currently to modulate Nrf2 activity thereby control the cancers. Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis.
- Author
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Jiang L, Chen XB, Wu Q, Zhu HY, Du CY, Ying MD, He QJ, Zhu H, Yang B, and Cao J
- Subjects
- Amino Acid Sequence, Animals, HEK293 Cells, Humans, Mice, Ferroptosis physiology, Protein Deglycase DJ-1 metabolism, Protein Multimerization physiology, Pyruvaldehyde metabolism
- Abstract
DJ-1 is a multifunctional protein associated with cancers and autosomal early-onset Parkinson disease. Besides the well-documented antioxidative stress activity, recent studies show that DJ-1 has deglycation enzymatic activity and anti-ferroptosis effect. It has been shown that DJ-1 forms the homodimerization, which dictates its antioxidative stress activity. In this study, we investigated the relationship between the dimeric structure of DJ-1 and its newly reported activities. In HEK293T cells with Flag-tagged and Myc-tagged DJ-1 overexpression, we performed deletion mutations and point mutations, narrowed down the most critical motif at the C terminus. We found that the deletion mutation of the last three amino acids at the C terminus of DJ-1 (DJ-1 ΔC3) disrupted its homodimerization with the hydrophobic L187 residue being of great importance for DJ-1 homodimerization. In addition, the ability in methylglyoxal (MGO) detoxification and deglycation was almost abolished in the mutation of DJ-1 ΔC3 and point mutant L187E compared with wild-type DJ-1 (DJ-1 WT). We also showed the suppression of erastin-triggered ferroptosis in DJ-1
-/- mouse embryonic fibroblast cells was abolished by ΔC3 and L187E, but partially diminished by V51C. Thus, our results demonstrate that the C terminus of DJ-1 is crucial for its homodimerization, deglycation activity, and suppression of ferroptosis.- Published
- 2021
- Full Text
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30. Çeşitli kaynaklarda peptid temelli deglikasyon ajanlarının araştırılması
- Author
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Kani, Hatice Kübra, Zihnioğlu, Figen, Fen Bilimleri Enstitüsü, and Biyokimya Anabilim Dalı
- Subjects
Glycation ,AGE ,Biyokimya ,Glikasyon ,Deglycation ,Bioactive Peptide 1 ,Biyoaktif-Peptid IV ,Biochemistry ,Deglikasyon - Abstract
Diabetes mellitus multifaktoriyel, kronik bir metabolizma hastalığıdır. Her geçen gün dünya popülasyonunda hastalığa maruz kalan kişilerin artması ile gerek hastalığın oluşumunun gerekse hastalık sonucunda gelişen nefropati, retinopati, nöropati, anjiyopati vb. komplikasyonların engellenmesine yönelik yeni tedavilerin geliştirilmesi bir zorunluluk halini almıştır. Bu bağlamda birçok araştırıcı tarafından farklı yönleriyle araştırılmaktadır. Hiperglisemide, glukoz ve proteinlerin amino grupları arasında kendiliğinden gelişen enzimatik olmayan glikasyon reaksiyonları yoluyla önce Schiff bazları, sonrasında daha stabil olan Amadori ürünleri oluşur. Amadori ürünlerinin oluşumundan sonra ileri glikasyon son ürünleri(AGE) meydana gelir. Son zamanlarda yapılan çalışmalarda AGE oluşumunun glukozun oto-oksidatif prosesine bağlı olduğu ve serbest oksijen radikallerinin oluşumunu etkiledikleri gösterilmiştir. İleri glikasyon son ürünleri olarak adlandırılan bu ürünlerin birikmesi ile doku proteinlerinde yapısal ve fonksiyonel değişiklikler oluşmaktadır. Sonuç olarak yaşlanma ve yaşlanmaya bağlı hastalıklar, diyabetik komplikasyonlar, romatoid artrit, nörodejeneratif hastalıklar vb. birçok önemli hastalığın patojenezinde önemli rol oynadıkları bilinmektedir. Bu nedenle enzimatik olmayan bu glikasyonun ve ileri glikasyon ürünlerinin oluşumunun engellenmesi son yıllarda üzerinde sıklıkla durulan konular arasındadır. Genel anlamda AGE oluşumunun inhibisyonunda diğerlerinin arasında en etkin olduğu düşünülen deglikasyon prosesi de enzimatik olmayan prosesin ilk ürünleri olan Schiff bazları (glikozaminler) üzerindendir. Bu deglikasyon prosesindeki ilk adım transglikasyon olarak adlandırılmaktadır ve şekerin Schiff bazından düşük molekül kütleli intraselüler nükleofillere transferini içerir. Transglikasyon ajanları sayesinde, glikasyon ilk evrelerinde tersine çevrilir. Bunu gerçekleştirebilme yeteneğine sahip bir bileşiğin etkinliği ne kadar fazla ise, yaşam süresini uzatmak ve kaliteli kılmak açısından önemli olacaktır. Bu bağlamda bu tez çalışmasında sistein ve histidince zengin bitkilerden deglikasyon etkinliği olan peptid yapıda bileşiklerin izolasyonu gerçekleştirilerek deglikasyon etkinliklerine bakıldı. Sonuç olarak hazırlanan bitki peptid izolatlarından sırasıyla soya, arpa, bağdem ve buğday'ın antiglikasyon etkinliklerinin karnozin ve aminoguanidin'e kıyasla kayda değer ölçüde etkin olduğu belirlendi. İncelenen tüm parametreler açısından değerlendirildiğinde ise soya peptid izolatının en iyi deglikasyon, antioksidan ve metal bağlama etkinliği olduğu saptanmış olup daha etkin ve seçimli inhibitörlerin geliştirilmesi açısından önemli olduğu düşünüldü., Diabetes mellitus is one of the most common diseases in most of the developed countries. It can affect nearly every organ and system in the body. Hyperglycemia in diabetes causes non enzymatic glycation of proteins and leads to their structural and functional changes, resulting in diabetic complications like nephropathy, retinopathy, neuropathy, and angiopathy. Glycation of proteins starts with the formation of Shiff's base, followed by intermolecular rearrangement and conversion into Amadori products. Amadori products undergo cross linkage to form a heterogeneous protein-bound moieties, termed as advanced glycated end products (AGEs). They have been recently demonstrated to be linked to glucose auto-oxidative process and may influence the generation of oxygen free radicals. The formation of AGEs is not only linked to diabetes but also to several diseases like Alzheimer's and age related diseases. Among others deglycation process acting on Shiff bases (glycosylamines) which are the first products of the nonenzymatic glycation. The first step in this deglycation process occurs by transfer of the sugar moiety from the Shiff base to one of the low-molecular weight intracellular nucleophiles. Any agent capaple of doing this, if potent, would be very important for life-extension, since glycation in the body can only be slowed down but not stopped. There are numerous publications describing the in vitro antiglycating affect of some peptides like glutathione, carnosine and its analogs, polyamines, thiols and thiolamines. Until now many efforts have been made to seek new AGE inhibitors, in particular those from natural sources without adverse effect. In this work is to investigate peptide based antiglycation agents from various sources that inhibit AGEs formation. Among all plant peptide isolates soybean was found to be most efficient by means of antiglycating, antioxidant and metal chelatation activity.
- Published
- 2017
31. Étude structurale de la fructoselysine 6-kinase d’Escherichia coli : reconnaissance de substrats et mécanisme enzymatique
- Author
-
Arthus-Cartier, Guillaume and Sygusch, Jurgen
- Subjects
PfkB ,Metabolism ,Métabolisme ,Fructoselysine 6-kinase ,Enzymatic mechanism ,Fructoselysine ,Mécanisme enzymatique ,Deglycation ,Déglycation - Abstract
Quelques enzymes sont connus pour déglyquer les kétoamines résultants de la réaction de Maillard entre des sucres et des amines primaires. Il a été démontré qu’Escherichia coli possède un opéron afin de métaboliser la fructoselysine. La fructoselysine 6-kinase, de la famille des PfkB, initie le processus de déglycation permettant l’utilisation ultérieure du glucose-6-P par la bactérie. La résolution de la structure de la FL6K par cristallographie et diffraction des rayons X a permis d’identifier son site actif en présence d’ATP, d’ADP et d’AMP-PNP. La modélisation de la fructoselysine au site actif de la kinase a permis d’identifier des résidus pouvant être importants pour sa liaison et son mécanisme enzymatique. De plus, les résultats de cinétique suggèrent que le mécanisme utilisé par la FL6K semble passer par un état ternaire de type SN2. Des modifications structurales à la FL6K pourraient permettre d’augmenter la taille des substrats afin de permettre ultimement la déglycation de protéines., Some enzymes have been found to deglycate the products of the Maillard reaction between sugars and primary amines: ketoamines. An operon is found in Escherichia coli that allows the growth on fructoselysine media. The deglycation process is done by a kinase and a “deglycase”. The fructoselysine 6-kinase, a member of the PfkB family, phosphorylates its substrate on the sixth carbon to initiate the metabolism of fructoselysine. Here are presented x-ray crystallography structures obtained for the fructoselysine 6-kinase in its native form and bound with ATP, ADP and AMP-PNP. The active site of the kinase has been determined, and modelisation of fructoselysine allowed identification of some residues that might be important for the specific binding of the substrate and the enzymatic mechanism. Kinetic results tend to suggest a SN2 mechanism for the phosphorylation catalyzed by the enzyme. Structural modifications of the FL6K could help to increase the size of the substrates recognized by the enzyme until it binds glycated proteins.
- Published
- 2010
32. Many fructosamine 3-kinase homologues in bacteria are ribulosamine/erythrulosamine 3-kinases potentially involved in protein deglycation
- Author
-
UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Gemayel, Rita, Fortpied, Juliette, Rzem, Rim, Vertommen, Didier, Veiga da Cunha, Maria, Van Schaftingen, Emile, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, Gemayel, Rita, Fortpied, Juliette, Rzem, Rim, Vertommen, Didier, Veiga da Cunha, Maria, and Van Schaftingen, Emile
- Abstract
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 approximately 200 (i.e. approximately 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.
- Published
- 2007
33. Variability in erythrocyte fructosamine 3-kinase activity in humans correlates with polymorphisms in the FN3K gene and impacts on haemoglobin glycation at specific sites.
- Author
-
UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service d'endocrinologie et de nutrition, Delpierre, Ghislain, Veiga da Cunha, Maria, Vertommen, Didier, Buysschaert, Martin, Van Schaftingen, Emile, UCL - MD/BICL - Département de biochimie et de biologie cellulaire, UCL - MD/MINT - Département de médecine interne, UCL - (SLuc) Service d'endocrinologie et de nutrition, Delpierre, Ghislain, Veiga da Cunha, Maria, Vertommen, Didier, Buysschaert, Martin, and Van Schaftingen, Emile
- Abstract
BACKGROUND: Part of the fructosamines that are bound to intracellular proteins are repaired by fructosamine 3-kinase (FN3K). Because subject-to-subject variations in erythrocyte FN3K activity could affect the level of glycated haemoglobin independently of differences in blood glucose level, we explored if such variability existed, if it was genetically determined by the FN3K locus on 17q25 and if the FN3K activity correlated inversely with the level of glycated haemoglobin. RESULTS: The mean erythrocyte FN3K activity did not differ between normoglycaemic subjects (n = 26) and type 1 diabetic patients (n = 31), but there was a wide interindividual variability in both groups (from about 1 to 4 mU/g haemoglobin). 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. There was no significant correlation between FN3K activity and the levels of HbA1c, total glycated haemoglobin (GHb) and haemoglobin fructoselysine residues, either in the normoglycaemic or diabetic group. However, detailed analysis of the glycation level at various sites in haemoglobin indicated that the glycation level of Lys-B-144 was about twice as high in normoglycaemic subjects with the lowest FN3K activities as compared to those with the highest FN3K activities. CONCLUSION: Interindividual variability of FN3K activity is substantial and impacts on the glycation level at specific sites of haemoglobin, but does not detectably affect the level of HbA1c or GHb. As FN3K opposes one of the chemical effects of hyperglycaemia, it would be of interest to test whether hypoactivity of this enzyme favours the development of diabetic complications.
- Published
- 2006
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