A hypothesis: FN3KRP (Fructosamine-3-Kinase-Related Protein) phosphorylates intermediates downstream from fructosamines in the pathway leading from glucose to glucosepane.

Benjamin Szwergold

doi:10.12688/f1000research.180252.1

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Opinion Article

A hypothesis: FN3KRP (Fructosamine-3-Kinase-Related Protein) phosphorylates intermediates downstream from fructosamines in the pathway leading from glucose to glucosepane.

[version 1; peer review: 1 not approved]

Benjamin Szwergold

PUBLISHED 12 May 2026

Author details Author details

Research, Seroclear LLC, Philadelpia, PA, 19106, USA

Benjamin Szwergold
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Fructosamine-3-kinase is a deglycating enzyme that reverses the glycation reaction by phosphorylating the first stable Maillard intermediate, fructosamine, to fructosamine-3-phosphate, thereby causing decomposition of that glycation adduct.

In this paper I propose that a close homolog of that kinase, fructosamine-3-phosphate-related protein, phosphorylates 3-ketosamine, a Maillard intermediate downstream from fructosamine, to 3-ketosamine-4-phosphate. This phosphorylation causes decomposition of the 3-ketosamine intermediate, providing thereby another mechanism for reversing the Maillard reaction.

Keywords

FN3K, FN3KRP, glycation, deglycation, glucosepane, Maillard reaction, fructosamine, ketosamine

Corresponding author: Benjamin Szwergold

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2026 Szwergold B. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Szwergold B. A hypothesis: FN3KRP (Fructosamine-3-Kinase-Related Protein) phosphorylates intermediates downstream from fructosamines in the pathway leading from glucose to glucosepane. [version 1; peer review: 1 not approved]. F1000Research 2026, 15:713 (https://doi.org/10.12688/f1000research.180252.1) First published: 12 May 2026, 15:713 (https://doi.org/10.12688/f1000research.180252.1) Latest published: 12 May 2026, 15:713 (https://doi.org/10.12688/f1000research.180252.1)

Introduction

Nonenzymatic reactions between glucose and proteins (Maillard reactions) are an unavoidable feature of life. These reactions have mostly adverse effects on proteins by inhibiting enzymes, interfering with receptor function, and crosslinking structural proteins such as collagen.^1,2 Traditionally, these reactions were thought to be totally nonenzymatic with no mechanisms to reverse or control them. This changed in the year 2000 with the discovery of Fructosamine-3-Kinase (FN3K)^3,4

This enzyme phosphorylates the first stable intermediates of the Maillard reaction, protein-bound fructosamines, to fructosamine-3-phosphates. Since these phosphoesters are intrinsically unstable, this reaction leads to decomposition of the glycation adducts, regeneration of an unmodified protein, and concomitant production of 3-deoxyglucosone.⁴

When FN3K was isolated in our laboratory, it copurified with another closely related protein that has an identical MW but a slightly lower isoelectric point (Fig. 1).⁴ At the time, this second protein was assumed to be an isozyme of FN3K with the same substrate specificity, namely D-fructosamine. Subsequent work revealed, however, that this enzyme, renamed Frucose-3-Kinase-Related Protein (FN3KRP), is quite distinct from FN3K because it does not phosphorylate D-fructosamines. Extensive work by Van-Schaftingen et al. has shown that FN3KRP phosphorylates a number of other Amadori products on the C3-hydroxyl. These include D-erythrulosamine, D-ribulosamine and D-psicosamine.⁵ While none of these ketosamines, nor their aldose precursors, are found in cells, Van Schaftingen et al. have suggested and documented ways in which they can be produced from erythrose-4-phosphate and ribose-5-phosphate by a combination of Maillard reactions of the phosphorylated metabolites and dephosphorylation of the resulting Amadori products by specific phosphatases.^6,7

Fig. 1. A) Activity of the purified proteins with an Amadori substrate preparation containing 95% fructosamine and small amounts of other materials.

The assay was conducted by measuring the incorporation of ³²P into the product from ³²P ATP. B) SDS PAGE of fractions from an isoelectric-focusing gel showing the IEF isoforms of FN3K and FN3KRP corresponding to the activity profile shown in panel A.

Subsequent to Van Schaftingen’s work, using recombinant FN3KRP, I was able to show that, in addition to the compounds identified above, FN3KRP also phosphorylates glucitolamines such as N-methylglucamine (meglumine).⁸ However, unlike the other substrates, this phosphorylation occurs on the C4-hydroxyl. This was a surprising result, the significance of which was not apparent until a recent closer re-examination of data on purified FN3K, as shown in Fig.1. As can be seen in figure, phosphorylating activities are evident with both FN3K and FN3KRP, even though the substrate used here is nominally just fructosamine. The activity of FN3K is easy to understand; however, the source of FN3KRP activity is not clear.

The most likely explanation for the phosphorylating activity of FN3KRP is that while the substrate used was nominally fructosamine, it was not completely homogeneous. As assessed at that time, it was only 95% pure but it probably also contained a compound (or compounds) that would be a substrate for FN3KRP. Given that the radioassay for FN3K used in these experiments contained saturating concentrations of fructosamine (1 mM vs. Km ~ 25 μM), it is likely that the FN3KRP substrate, even if present as only a small fraction in this preparation, would be phosphorylated sufficiently (by FN3KRP) to be detected.

Several candidates for the identity of this “contaminant” substrate are shown in Fig. 2, including the following:

I) A Schiff base of the amine with glucose
II) A di-fructosamine adduct
III) A glycation intermediate downstream of fructosamine, namely 3-keto-D-glucitolamine.

Fig. 2. Structures of the possible contaminants of the fructosamine substrate which could, hypothetically, be substrates of FN3KR.

Hypothesis

I propose that the physiological substrate of FN3KRP is 3-keto-D-glucolamine (3-ketosamine) produced from fructosamine by migration of the C2-carbonyl to the C3 position (Fig. 3), The product of this reaction, 3-ketosamine-4-phosphate, is intrisically unstable and decomposes to regenerate an unmodified protein along with a concomitant production of a tricarbonyl, 5,6-dihydoxy-2,3-dioxohexanal (Fig. 4).

Fig. 3. Some initial steps in the reaction between an amine and glucose leading from a Schiff base to fructosamine, then to 3-ketosamine and eventually to glucosepane.

Fig. 4. Proposed function of FN3KRP as a deglycating enzyme.

A) 3-ketosamine is phosphdrylated by FN3KRP to 3-ketosamine-4-phosphate. B) Due to its structure, 3-ketosamine-4-phosphate decomposes by-elimination of phosphate to 4-deoxy-3-ketosamine. C) In a reverse Schiff reaction, 4-deoxy-3-ketosamine dissociates to an unmodified amine (protein) along with the production of a tricarbobyl, 4,5-dihydroxy-2,3-dioxohexanal (compound D). This tricarbonyl group is then reduced to 4-deoxyglucosone (compound E) and/or oxidized to 4-deoxy-2,3-dioxogluuconic acid (compound F).

Support for the hypothesis

A) Based on the work of Lederer et al.,^9,10 it is clear that during the Maillard reaction of glucose with an amine, the carbonyl moieties of the sugar migrate rapidly along its backbone from C2 to C3 and onwards. Thus, it is very likely that in an Amadori preparation, synthesized by condensation of an amine with glucose, some ketosamines with C3, C4, C5, and C6 carbonyls will be present. Since 3-ketosamine (−3-ketohexitolamine) is a glycation intermediate directly downstream of fructosamine, it is a good candidate as a substrate for FN3KRP and would be phosphorylated at C4.
B) Given the ability of FN3KR to phosphorylate N-glucitolamines on the C4 hydroxyl, its suggested function as a 4-kinase of 3-ketosamines is consistent with the fact that its close homolog, FN3K, acts as a 3-kinase not only with fructosamines but also with glucitols and glucitol amines.^8,11–13

Experimental confirmations of the hypothesis

A) Testing this hypothesis should be straightforward, requiring only the synthesis of an Amadori product using glucose and an amine and the use of recombinant KN3KRP produced in HEK193 cells.^14,15 Since FN3KRP does not phosphorylate fructosamines, a reaction of the recombinant enzyme with high concentrations of the Amadori product (~ 50 mM) is likely to result in the phosphorylation of a small amount of substrate present in the preparation. The ¹H decoupled ³¹P NMR spectrum of the reaction mixture revealed several peaks attributed only to the phosphorylated substrate. In the proton-coupled ³¹P NMR spectrum, these peaks split into doublets with a coupling constant of ~10 Hz.
B) Secondary tests of the hypothesis will involve determination of the decomposition rates of the phosphorylated substrate(s) and identification of byproducts that should include tricarbonyl (5,6-dihydroxy-2,3-dioxohexanal) as well as its reduced and oxidized metabolites, 4-deoxyglucosone and 4-deoxy-2,3-dioxogluconic acid (Fig.4).

Reservations about the hypothesis

There is little doubt that the Maillard reaction between an amine and glucose produces substrate(s) for FN3KRP. However, even if that compound is not 3-ketosamine, identifying the physiological substrate of FN3KRP is still worthwhile.

Implications

If my hypothesis proves correct, then, at the very least, it will provide some new insights into the process of intracellular Maillard reactions and their control. Moreover, given the number of recent publications linking FN3KRP to a number of interesting phenotypes,^16–21 the potential impact of this finding may prove to be substantial.

Data availability statement

No data are associated with this article.

References

1. Henning C, Glomb MA: Pathways of the Maillard reaction under physiological conditions. Glycoconjugate journal. 2016; 33(4): 499–512. PubMed Abstract | Publisher Full Text
2. Tessier FJ: The Maillard reaction in the human body. The main discoveries and factors that affect glycation. Pathologie Biologie. 2010; 58(3): 214–219. PubMed Abstract | Publisher Full Text
3. Delpierre G, Rider MH, Collard F, et al.: Identification, cloning, and heterologous expression of a mammalian fructosamine-3- kinase. Diabetes. 2000; 49(10): 1627–1634. Publisher Full Text
4. Szwergold BS, Howell S, Beisswenger PJ: Human fructosamine-3- kinase: purification, sequencing, substrate specificity, and evidence of activity in vivo. Diabetes. 2001; 50(9): 2139–2147. Publisher Full Text
5. Collard F, Delpierre G, Stroobant V, et al.: A mammalian protein homologous to fructosamine-3-kinase is a ketosamine-3-kinase acting on psicosamines and ribulosamines but not on fructosamines. Diabetes. 2003; 52(12): 2888–2895. Publisher Full Text
6. Fortpied J, Gemayel R, Vertommen D, et al.: Identification of protein-ribulosamine-5-phosphatase as human low-molecular-mass protein tyrosine phosphatase-A. Biochem J. 2007; 406(1): 139–145. PubMed Abstract | Publisher Full Text | Free Full Text
7. Gemayel R, Fortpied J, Rzem R, et al.: Many fructosamine 3-kinase homologues in bacteria are ribulosamine/erythrulosamine 3-kinases potentially involved in protein deglycation. The FEBS Journal. 2007; 274(17): 4360–4374. PubMed Abstract | Publisher Full Text
8. Szwergold B, Manevich Y, Payne L, et al.: Fructosamine-3-kinase- related-protein phosphorylates glucitolamines on the C-4 hydroxyl: Novel substrate specificity of an enigmatic enzyme. Biochem Biophys Res Commun. 2007; 361(4): 870–875. Publisher Full Text
9. Biemel KM, Conrad J, Lederer MO: Unexpected carbonyl mobility in aminoketoses: the key to major Maillard crosslinks. Angew Chem Int Ed Engl. 2002; 41(5): 801–804.
10. Reihl O, Rothenbacher TM, Lederer MO, et al.: Carbohydrate carbonyl mobility––the key process in the formation of α-dicarbonyl intermediates. Carbohydrate research. 2004; 339(9): 1609–1618. Publisher Full Text
11. Petersen A, Szwergold BS, Kappler F, et al.: Identification of sorbitol 3-phosphate and fructose 3-phosphate in normal and diabetic human erythrocytes. J Biol Chem. 1990; 265(29): 17424–7.
12. Petersen A, Kappler F, Szwergold BS, et al.: Fructose metabolism in the human erythrocyte. Phosphorylation to fructose 3-phosphate. Biochemical Journal. 1992; 284(2): 363–366. PubMed Abstract | Publisher Full Text | Free Full Text
13. Delpierre G, Vanstapel F, Stroobant V, et al.: Conversion of a synthetic fructosamine into its 3-phospho derivative in human erythrocytes. Biochem J. 2000; 352(3): 835–839. Publisher Full Text
14. http
15. http
16. Alderawi A, Caramori G, Baker EH, et al.: FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease. BMJ Open Respir Res. 2020; 7(1). Publisher Full Text
17. Benton MC, Lea RA, Macartney-Coxson D, et al.: Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits. The American Journal of Human Genetics. 2013; 93(6): 1087–1099. PubMed Abstract | Publisher Full Text | Free Full Text
18. Kwon MJ, Kim JH, Lee JY, et al.: Genetic Polymorphisms in the 3′- Untranslated Regions of SMAD5, FN3KRP, and RUNX-1 Are Associated with Recurrent Pregnancy Loss. Biomedicines. 2022; 10(7): 1481. PubMed Abstract | Publisher Full Text | Free Full Text
19. Cheng YF, Yang CY, Tsai MC: Shared Genetics between Age at Menarche and Type 2 Diabetes Mellitus: Genome-Wide Genetic Correlation Study. Biomedicines. 2024; 12(1): 157. PubMed Abstract | Publisher Full Text | Free Full Text
20. Torres GG, Nygaard M, Caliebe A, et al.: Exome-wide association study identifies FN3KRP and PGP as new candidate longevity genes. J Gerontol A Biol Sci Med Sci. 2021; 76(5): 786–795.
21. Shrestha S, Taujale R, Katiyar S, et al.: Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways. NPJ Syst Biol Appl. 2024; 10(1): 64.

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Version 1

VERSION 1 PUBLISHED 12 May 2026

Author details Author details

Research, Seroclear LLC, Philadelpia, PA, 19106, USA

Benjamin Szwergold
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Visualization, Writing – Original Draft Preparation

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

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Published: 12 May 2026, 15:713

https://doi.org/10.12688/f1000research.180252.1

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© 2026 Szwergold B. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Szwergold B. A hypothesis: FN3KRP (Fructosamine-3-Kinase-Related Protein) phosphorylates intermediates downstream from fructosamines in the pathway leading from glucose to glucosepane. [version 1; peer review: 1 not approved]. F1000Research 2026, 15:713 (https://doi.org/10.12688/f1000research.180252.1)

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Reviewer Report 09 Jun 2026

Kerry Loomes, University of Auckland, Auckland, New Zealand

Not Approved

https://doi.org/10.5256/f1000research.198849.r485258

Unfortunately, this manuscript does not move knowledge forward from the author's previous peer-reviewed paper. In 2021, the author published a highly similar paper titled: "A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines" in the journal, Rejuvenation ... Continue reading

Unfortunately, this manuscript does not move knowledge forward from the author's previous peer-reviewed paper. In 2021, the author published a highly similar paper titled: "A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines" in the journal, Rejuvenation Research.

The submitted manuscript is essentially a restatement of the same downstream phosphorylation model in this 2021 paper without any clear differentiation. This precludes indexing in its present form.

The manuscript correctly identifies the core issue of non-enzymatic glycation (the Maillard reaction) and the physiological necessity of deglycation pathways to neutralize macromolecular damage caused by chronic hyperglycemia. The evolutionary preservation of FN3K and FN3KRP as ancient housekeeping genes across diverse taxa is consistent with literature highlighting cell maintenance roles.

The primary scientific deficiency in this manuscript is its failure to properly context-shift from the author's previous peer-reviewed literature. In 2021, the author published a highly similar paper titled: "A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines". This paper was not cited in the submitted manuscript.

Comparing the submitted manuscript to this published 2021 paper, the text reveals significant overlap in conceptual framing, wording, and figures. Specifically, Figure 4 in the manuscript is essentially the same as Figure 4 in the 2021 publication. To progress this hypothesis paper toward indexing, this opinion article should provide a distinct advancement, updated perspective, or newly emerging data to justify its indexing. Re-hypothesizing the same downstream phosphorylation model without clear differentiation compromises its standing in the current literature. There must be a clear differentiation from the paper published in Rejuvenation Research (2021) and the naming nomenclature used should also be consistent across the publications as well as incorporation of appropriate reference citations.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Are arguments sufficiently supported by evidence from the published literature?

Partly
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Partly

References

1. Szwergold B: A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines. Rejuvenation Research. 2021; 24 (4): 310-318 Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Metabolic disease, mechanism underlying diabetic complications, cancer metabolism, natural product biochemistry

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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09 Jun 2026 | for Version 1

Kerry Loomes, University of Auckland, Auckland, New Zealand

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Not Approved

Unfortunately, this manuscript does not move knowledge forward from the author's previous peer-reviewed paper. In 2021, the author published a highly similar paper titled: "A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines" in the journal, Rejuvenation Research.

The submitted manuscript is essentially a restatement of the same downstream phosphorylation model in this 2021 paper without any clear differentiation. This precludes indexing in its present form.

The manuscript correctly identifies the core issue of non-enzymatic glycation (the Maillard reaction) and the physiological necessity of deglycation pathways to neutralize macromolecular damage caused by chronic hyperglycemia. The evolutionary preservation of FN3K and FN3KRP as ancient housekeeping genes across diverse taxa is consistent with literature highlighting cell maintenance roles.

The primary scientific deficiency in this manuscript is its failure to properly context-shift from the author's previous peer-reviewed literature. In 2021, the author published a highly similar paper titled: "A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines". This paper was not cited in the submitted manuscript.

Comparing the submitted manuscript to this published 2021 paper, the text reveals significant overlap in conceptual framing, wording, and figures. Specifically, Figure 4 in the manuscript is essentially the same as Figure 4 in the 2021 publication. To progress this hypothesis paper toward indexing, this opinion article should provide a distinct advancement, updated perspective, or newly emerging data to justify its indexing. Re-hypothesizing the same downstream phosphorylation model without clear differentiation compromises its standing in the current literature. There must be a clear differentiation from the paper published in Rejuvenation Research (2021) and the naming nomenclature used should also be consistent across the publications as well as incorporation of appropriate reference citations.

Is the topic of the opinion article discussed accurately in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Are arguments sufficiently supported by evidence from the published literature?

Partly
Are the conclusions drawn balanced and justified on the basis of the presented arguments?

Partly

References

1. Szwergold B: A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines. Rejuvenation Research. 2021; 24 (4): 310-318 Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Metabolic disease, mechanism underlying diabetic complications, cancer metabolism, natural product biochemistry

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Respond to this report

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[1] 1. Henning C, Glomb MA: Pathways of the Maillard reaction under physiological conditions. Glycoconjugate journal. 2016; 33(4): 499–512. PubMed Abstract | Publisher Full Text

[2] 2. Tessier FJ: The Maillard reaction in the human body. The main discoveries and factors that affect glycation. Pathologie Biologie. 2010; 58(3): 214–219. PubMed Abstract | Publisher Full Text

[3] 3. Delpierre G, Rider MH, Collard F, et al.: Identification, cloning, and heterologous expression of a mammalian fructosamine-3- kinase. Diabetes. 2000; 49(10): 1627–1634. Publisher Full Text

[4] 4. Szwergold BS, Howell S, Beisswenger PJ: Human fructosamine-3- kinase: purification, sequencing, substrate specificity, and evidence of activity in vivo. Diabetes. 2001; 50(9): 2139–2147. Publisher Full Text

[5] 5. Collard F, Delpierre G, Stroobant V, et al.: A mammalian protein homologous to fructosamine-3-kinase is a ketosamine-3-kinase acting on psicosamines and ribulosamines but not on fructosamines. Diabetes. 2003; 52(12): 2888–2895. Publisher Full Text

[6] 6. Fortpied J, Gemayel R, Vertommen D, et al.: Identification of protein-ribulosamine-5-phosphatase as human low-molecular-mass protein tyrosine phosphatase-A. Biochem J. 2007; 406(1): 139–145. PubMed Abstract | Publisher Full Text | Free Full Text

[7] 7. Gemayel R, Fortpied J, Rzem R, et al.: Many fructosamine 3-kinase homologues in bacteria are ribulosamine/erythrulosamine 3-kinases potentially involved in protein deglycation. The FEBS Journal. 2007; 274(17): 4360–4374. PubMed Abstract | Publisher Full Text

[8] 8. Szwergold B, Manevich Y, Payne L, et al.: Fructosamine-3-kinase- related-protein phosphorylates glucitolamines on the C-4 hydroxyl: Novel substrate specificity of an enigmatic enzyme. Biochem Biophys Res Commun. 2007; 361(4): 870–875. Publisher Full Text

[9] 9. Biemel KM, Conrad J, Lederer MO: Unexpected carbonyl mobility in aminoketoses: the key to major Maillard crosslinks. Angew Chem Int Ed Engl. 2002; 41(5): 801–804.

[10] 10. Reihl O, Rothenbacher TM, Lederer MO, et al.: Carbohydrate carbonyl mobility––the key process in the formation of α-dicarbonyl intermediates. Carbohydrate research. 2004; 339(9): 1609–1618. Publisher Full Text

[11] 11. Petersen A, Szwergold BS, Kappler F, et al.: Identification of sorbitol 3-phosphate and fructose 3-phosphate in normal and diabetic human erythrocytes. J Biol Chem. 1990; 265(29): 17424–7.

[12] 12. Petersen A, Kappler F, Szwergold BS, et al.: Fructose metabolism in the human erythrocyte. Phosphorylation to fructose 3-phosphate. Biochemical Journal. 1992; 284(2): 363–366. PubMed Abstract | Publisher Full Text | Free Full Text

[13] 13. Delpierre G, Vanstapel F, Stroobant V, et al.: Conversion of a synthetic fructosamine into its 3-phospho derivative in human erythrocytes. Biochem J. 2000; 352(3): 835–839. Publisher Full Text

[14] 14. http

[15] 15. http

[16] 16. Alderawi A, Caramori G, Baker EH, et al.: FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease. BMJ Open Respir Res. 2020; 7(1). Publisher Full Text

[17] 17. Benton MC, Lea RA, Macartney-Coxson D, et al.: Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits. The American Journal of Human Genetics. 2013; 93(6): 1087–1099. PubMed Abstract | Publisher Full Text | Free Full Text

[18] 18. Kwon MJ, Kim JH, Lee JY, et al.: Genetic Polymorphisms in the 3′- Untranslated Regions of SMAD5, FN3KRP, and RUNX-1 Are Associated with Recurrent Pregnancy Loss. Biomedicines. 2022; 10(7): 1481. PubMed Abstract | Publisher Full Text | Free Full Text

[19] 19. Cheng YF, Yang CY, Tsai MC: Shared Genetics between Age at Menarche and Type 2 Diabetes Mellitus: Genome-Wide Genetic Correlation Study. Biomedicines. 2024; 12(1): 157. PubMed Abstract | Publisher Full Text | Free Full Text

[20] 20. Torres GG, Nygaard M, Caliebe A, et al.: Exome-wide association study identifies FN3KRP and PGP as new candidate longevity genes. J Gerontol A Biol Sci Med Sci. 2021; 76(5): 786–795.

[21] 21. Shrestha S, Taujale R, Katiyar S, et al.: Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways. NPJ Syst Biol Appl. 2024; 10(1): 64.

A hypothesis: FN3KRP (Fructosamine-3-Kinase-Related Protein) phosphorylates intermediates downstream from fructosamines in the pathway leading from glucose to glucosepane.

Abstract

Keywords

Introduction

Fig. 1. A) Activity of the purified proteins with an Amadori substrate preparation containing 95% fructosamine and small amounts of other materials.

Fig. 2. Structures of the possible contaminants of the fructosamine substrate which could, hypothetically, be substrates of FN3KR.

Hypothesis

Fig. 3. Some initial steps in the reaction between an amine and glucose leading from a Schiff base to fructosamine, then to 3-ketosamine and eventually to glucosepane.

Fig. 4. Proposed function of FN3KRP as a deglycating enzyme.

Support for the hypothesis

Experimental confirmations of the hypothesis

Data availability statement

References

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