Modulation of in vivo 3-deoxyglucosone levels

Brown, Truman R.; Su, Bangying; Brown, Kerry; Schwartz, Michael A.; Tobia, Annette M.; Kappler, Francis

doi:10.1042/bst0311433

Cited by 16 publications

(5 citation statements)

References 19 publications

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“…Increased 3-DG has been shown to lead to a threefold increase in kidney lesions after 3 days in a rat model [32]. Among the patients in our study, we observed an eightfold increase in serum 3-DG after receiving 1.7 l of GDP-containing infusion fluid.…”

Section: Discussionsupporting

confidence: 54%

Infusion fluids contain harmful glucose degradation products

et al. 2010

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PurposeGlucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients’ blood.MethodsThe content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated.ResultsAll investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing.ConclusionsThese findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-010-1873-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 54%

Infusion fluids contain harmful glucose degradation products

et al. 2010

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“…Although the functions of FN3K homologs in lower eukaryotes and bacteria are yet to be equivocally established, it is proposed that they repair proteins modified by ribose-5-phosphate, a potent glycating agent generated by the metabolic pentose phosphate pathway (6,12,14,15). FN3K activity is essential for normal cellular functions, and uncontrolled activity can result in altered cellular homeostasis and disease (16,17). For example, accumulation of 3-deoxyglucosone, a by-product of human FN3K (HsFN3K) activity, is causatively associated with diabetic complications, such as retinopathy and neuropathy (18,19), and the development of hepatocellular carcinoma is dependent on the deglycation of nuclear transcription factor NRF2 (encoded by nuclear factor erythroid-derived 2-like 2 gene; NFE2L2) by HsFN3K (20).…”

Section: Introductionmentioning

confidence: 99%

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

et al. 2020

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Aberrant regulation of metabolic kinases by altered redox homeostasis substantially contributes to aging and various diseases, such as diabetes. We found that the catalytic activity of a conserved family of fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases, is regulated by redox-sensitive cysteine residues in the kinase domain. The crystal structure of the FN3K homolog from Arabidopsis thaliana revealed that it forms an unexpected strand-exchange dimer in which the ATP-binding P-loop and adjoining β strands are swapped between two chains in the dimer. This dimeric configuration is characterized by strained interchain disulfide bonds that stabilize the P-loop in an extended conformation. Mutational analysis and solution studies confirmed that the strained disulfides function as redox “switches” to reversibly regulate the activity and dimerization of FN3K. Human FN3K, which contains an equivalent P-loop Cys, was also redox sensitive, whereas ancestral bacterial FN3K homologs, which lack a P-loop Cys, were not. Furthermore, CRISPR-mediated knockout of FN3K in human liver cancer cells altered the abundance of redox metabolites, including an increase in glutathione. We propose that redox regulation evolved in FN3K homologs in response to changing cellular redox conditions. Our findings provide insights into the origin and evolution of redox regulation in the protein kinase superfamily and may open new avenues for targeting human FN3K in diabetic complications.

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“…Since the protein deglycation pathway is predominated by FN3K, it has been suggested by Brown et al [2003] that it may be possible, using FN3K specific inhibitors, to reduce the formation of 3-DG. 1-Deoxy-1-morpholinofructose (DMF) was originally employed as an FN3K inhibitor (K i 5 100 mM) for demonstrating the enzymatic process of hemoglobin deglycation, but DMF is, in fact, a substrate (K m 5 100 mM) for FN3K [Delpierre et al, 2000b[Delpierre et al, , 2002Delpierre and Van Schaftingen, 2003].…”

Section: Introductionmentioning

confidence: 99%

A new inhibitor for fructosamine 3‐kinase (Amadorase)

Tsai¹,

Chou²,

Kappler³

et al. 2006

Drug Development Research

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Non-enzymatic glycation is a Maillard reaction that occurs spontaneously between glucose and proteins and results in the accumulation of advanced glycation end products (AGEs), which are believed to be one of the causes for age-related tissue damage. Fructosamine 3-kinase (FN3K) is an enzyme involved in the protein deglycation process by fructosyl phosphorylation, returning amino acid residues to their pristine state with 3-deoxyglucosone (3-DG) and inorganic phosphate as by-products. 3-DG is a very reactive electrophile that is even more potent at generating AGEs than glucose; therefore, inhibitors specific to FN3K have been suggested as a means to suppress 3-DG formation. Dyn-12 is a substrate mimicking inhibitor with an IC 50 value of approximately 6 mM. We report a new hydrophobic competitive inhibitor with respect to fructolysine that has an IC 50 of 1.7 mM. Drug Dev. Res. 67:448-455, 2006.

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Modulation of in vivo 3-deoxyglucosone levels

Cited by 16 publications

References 19 publications

Infusion fluids contain harmful glucose degradation products

Infusion fluids contain harmful glucose degradation products

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

A new inhibitor for fructosamine 3‐kinase (Amadorase)

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