Fructosamine-3-kinase-related-protein phosphorylates glucitolamines on the C-4 hydroxyl: Novel substrate specificity of an enigmatic enzyme

Szwergold, Benjamin S.; Manevich, Yefim; Payne, Leo S.; Loomes, Kerry M.

doi:10.1016/j.bbrc.2007.07.127

Cited by 9 publications

(3 citation statements)

References 34 publications

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“…FN3K-RP phosphorylates ribulosamines, erythrulosamines, psicosamines, and glucitolamines but, unlike FN3K, does not phosphorylate fructosamines (41, 44). FN3K-RP is not inhibited by DMF, a competitive inhibitor of FN3K (43).…”

Section: Discussionmentioning

confidence: 99%

Purification and Identification of Activating Enzymes of CS-0777, a Selective Sphingosine 1-Phosphate Receptor 1 Modulator, in Erythrocytes

Yonesu

Kubota

Tamura

et al. 2011

Journal of Biological Chemistry

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CS-0777 is a selective sphingosine 1-phosphate (S1P) receptor 1 modulator with potential benefits in the treatment of autoimmune diseases, including multiple sclerosis. CS-0777 is a prodrug that requires phosphorylation to an active S1P analog, similar to the first-in-class S1P receptor modulator FTY720 (fingolimod). We sought to identify the kinase(s) involved in phosphorylation of CS-0777, anticipating sphingosine kinase (SPHK) 1 or 2 as likely candidates. Unlike kinase activity for FTY720, which is found predominantly in platelets, CS-0777 kinase activity was found mainly in red blood cells (RBCs). N,N-Dimethylsphingosine, an inhibitor of SPHK1 and -2, did not inhibit CS-0777 kinase activity. We purified CS-0777 kinase activity from human RBCs by more than 10,000-fold using ammonium sulfate precipitation and successive chromatography steps, and we identified fructosamine 3-kinase (FN3K) and fructosamine 3-kinase-related protein (FN3K-RP) by mass spectrometry. Incubation of human RBC lysates with 1-deoxy-1-morpholinofructose, a competitive inhibitor of FN3K, inhibited ∼10% of the kinase activity, suggesting FN3K-RP is the principal kinase responsible for activation of CS-0777 in blood. Lysates from HEK293 cells overexpressing FN3K or FN3K-RP resulted in phosphorylation of CS-0777 and structurally related molecules but showed little kinase activity for FTY720 and no kinase activity for sphingosine. Substrate preference was highly correlated among FN3K, FN3K-RP, and rat RBC lysates. FN3K and FN3K-RP are known to phosphorylate sugar moieties on glycosylated proteins, but this is the first report that these enzymes can phosphorylate hydrophobic xenobiotics. Identification of the kinases responsible for CS-0777 activation will permit a better understanding of the pharmacokinetics and pharmacodynamics of this promising new drug.

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Section: Discussionmentioning

confidence: 99%

Purification and Identification of Activating Enzymes of CS-0777, a Selective Sphingosine 1-Phosphate Receptor 1 Modulator, in Erythrocytes

Yonesu

Kubota

Tamura

et al. 2011

Journal of Biological Chemistry

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“…In human erythrocytes, FN3K mediates the phosphorylation of sorbitol or fructose and generates sorbitol-3-phosphate and fructose-3-phosphate, respectively [86,172,173]. Thus, both FN3K and FN3K-RP possess unique substrate specificity to phosphorylate protein-bound ketosamines [174]. BLAST searches demonstrated a set of proteins involved in encoding microbial sequences that share nearly 30% sequence homology with human FN3K [85].…”

Section: Fructosamine Kinases (Fn3k and Fn3k-rp) In The Regulation Of Cancersmentioning

confidence: 99%

The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

Beeraka

Bovilla

Doreswamy

et al. 2021

Cancers

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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.

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“…Previous methods are suitable for partially purified FN3K-RP only. They include 31 P-NMR of phosphorylation products [17] and the incorporation of radioactivity from 32 P-ATP into allose-derived Amadori compounds [18].…”

Section: Introductionmentioning

confidence: 99%

A new HPLC-based assay for the measurement of fructosamine-3-kinase (FN3K) and FN3K-related protein activity in human erythrocytes

Hellwig

Scherber

Koehler

et al. 2014

Clinical Chemistry and Laboratory Medicine

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Fructosamine-3-kinase-related-protein phosphorylates glucitolamines on the C-4 hydroxyl: Novel substrate specificity of an enigmatic enzyme

Cited by 9 publications

References 34 publications

Purification and Identification of Activating Enzymes of CS-0777, a Selective Sphingosine 1-Phosphate Receptor 1 Modulator, in Erythrocytes

Purification and Identification of Activating Enzymes of CS-0777, a Selective Sphingosine 1-Phosphate Receptor 1 Modulator, in Erythrocytes

The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

A new HPLC-based assay for the measurement of fructosamine-3-kinase (FN3K) and FN3K-related protein activity in human erythrocytes

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