DYN 12, a Small Molecule Inhibitor of the Enzyme Amadorase, Lowers Plasma 3-Deoxyglucosone Levels in Diabetic Rats

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

doi:10.1089/15209150152811234

Cited by 7 publications

(7 citation statements)

References 30 publications

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“…3-fold increase in 3DG observed in the tubules of normal rats on the same diet suggests that the dose-response relationship is in the correct range for 3DG to be a significant agent in stimulating kidney lesion formation in these susceptible rats. It is impossible to know whether the mechanism is direct adduct formation on DNA, excess production of various growth factors by 3DG [24], or some other effect. Further work is needed to confirm these observations and identify the causal pathway.…”

Section: Discussionmentioning

confidence: 99%

Modulation of in vivo 3-deoxyglucosone levels

Brown

et al. 2003

Biochemical Society Transactions

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Fructoselysine 3-phosphate is synthesized in vivo by the recently discovered fructoseamine-3-kinase (F3K) from fructoselysine and ATP and decomposes to lysine, P(i) and 3-deoxyglucosone (3DG). This pathway appears to dominate 3DG production in vivo, making it possible to modulate 3DG levels by stimulating or inhibiting the reaction. Present inhibitors are non-reacting substrate analogues with relatively high K (i) values and can inhibit F3K sufficiently in vivo to reduce 3DG in diabetic rat plasma by approx. 50%. Stimulation of the F3K pathway by feeding glycated casein causes an increase of 10-20-fold in plasma levels of 3DG and 3-fold in kidney tubules. Consequences of this increase were studied in two systems: the Eker rat, a model of susceptible kidney tubules; and birth rates in two rat strains. In both cases substantial pathological effects were observed. In the Eker rats, an approx. 3-fold increase in kidney lesions was observed ( P <0.00001). In both Fischer 344 and Sprague-Dawley rats, birth rates were reduced by 56% ( P <0.0001) and 12% ( P <0.015) respectively. These results suggest that inhibition of F3K is a promising new therapeutic target for diabetic complications, as well as other 3DG-dependent pathologies.

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Section: Discussionmentioning

confidence: 99%

Modulation of in vivo 3-deoxyglucosone levels

Brown

et al. 2003

Biochemical Society Transactions

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“…As mentioned above, one of the reaction products of this enzyme, 3-deoxyglucosone, is a highly reactive dicarbonyl sugar, which has been postulated to lead to the development of diabetic complications. Interestingly, a small molecule inhibitor of fructosamine 3-kinase, DYN12, lowers the plasma 3-deoxyglucosone levels in diabetic rats and possibly reduces the development of diabetic complications [59]. 3-deoxyglucosone has been proposed to play a role in the pathogenesis of diabetic complications [61].…”

Section: Protein Deglycationmentioning

confidence: 99%

Enzymatic deglycation of proteins

Monnier

2003

Archives of Biochemistry and Biophysics

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“…Fructosamine kinases phosphorylate the Amadori products prior to cleavage. Mammalian enzymes add the phosphate at C-3, and the product subsequently undergoes autocatalytic degradation (20). However, Escherichia coli and Bacillus subtilis kinases phosphorylate at C-6; further processing of such intermediates needs a second deglycase enzyme catalyzing the cleavage of the fructosamine 6-phosphates to generate, for example, glucose 6-phosphate and a free amine.…”

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confidence: 99%

Genetic Control of Amadori Product Degradation in Bacillus subtilis via Regulation of frlBONMD Expression by FrlR

Deppe

Klatte

Bongaerts

et al. 2011

Appl Environ Microbiol

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Bacillus subtilis is capable of degrading fructosamines. The phosphorylation and the cleavage of the resulting fructosamine 6-phosphates is catalyzed by the frlD and frlB gene products, respectively. This study addresses the physiological importance of the frlBONMD genes (formerly yurPONML), revealing the necessity of their expression for growth on fructosamines and focusing on the complex regulation of the corresponding transcription unit. In addition to the known regulation by the global transcriptional regulator CodY, the frl genes are repressed by the convergently transcribed FrlR (formerly YurK). The latter causes repression during growth on substrates other than fructosamines. Additionally, we identified in the first intergenic region of the operon an FrlR binding site which is centrally located within a 38-bp perfect palindromic sequence. There is genetic evidence that this sequence, in combination with FrlR, contributes to the remarkable decrease in the transcription downstream of the first gene of the frl operon.Amadori products (fructosamines), the first stable intermediates of the Maillard reaction, result from nonenzymatic glycation of amino acids or proteins with reducing sugars such as glucose. As Amadori products are found in heated food and cause several diseases in connection with diabetes and aging (4), enzymes catalyzing the degradation of Amadori products are of interest to industry and medicine for food processing and diagnostic purposes.There are two enzymatic mechanisms for the deglycation of Amadori products (reviewed in reference 7): fructosyl-amino acid oxidases (known as Amadoriases) and fructosamine kinases. The former deglycate by means of oxidation, generating the corresponding amino acid, glucosone, and H 2 O 2 . Amadoriases have been found in Aspergillus and Penicillium spp. (38, 42) but also in bacteria such as Arthrobacter and Corynebacterium spp. (9, 32). Fructosamine kinases phosphorylate the Amadori products prior to cleavage. Mammalian enzymes add the phosphate at C-3, and the product subsequently undergoes autocatalytic degradation (20). However, Escherichia coli and Bacillus subtilis kinases phosphorylate at C-6; further processing of such intermediates needs a second deglycase enzyme catalyzing the cleavage of the fructosamine 6-phosphates to generate, for example, glucose 6-phosphate and a free amine.E. coli grows on fructosyl-lysine as the sole carbon and nitrogen source, and expression of frlD (encoding the kinase) and frlB (encoding the deglycating protein) is induced by fructosyl-lysine (39). In B. subtilis, frlD and frlB belong to a gene cluster which additionally comprises three genes coding for putative transporters (frlONM) as well as the convergently oriented putative repressor gene frlR (Fig. 1). Substrate specificities of FrlD and FrlB are quite different than those of the enzymes of E. coli, as B. subtilis acts on ␣-glycated amino acids rather than on ε-glycated lysine (catalytic efficiencies Ͼ30-fold higher), the latter being the preferred substrate of the E...

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DYN 12, a Small Molecule Inhibitor of the Enzyme Amadorase, Lowers Plasma 3-Deoxyglucosone Levels in Diabetic Rats

Cited by 7 publications

References 30 publications

Modulation of in vivo 3-deoxyglucosone levels

Modulation of in vivo 3-deoxyglucosone levels

Enzymatic deglycation of proteins

Genetic Control of Amadori Product Degradation in Bacillus subtilis via Regulation of frlBONMD Expression by FrlR

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