Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency
14/01/2019
In a study led by Prof. Emile Van Schaftingen (WELBIO investigator at Université Catholique de Louvain), scientists showed that 2 rare genetic diseases leading to an abnormally low concentration of neutrophils  in the blood (neutropenia) are due to a lack of metabolic repair which causes the accumulation of a toxic product. The results of this study have been published in PNAS.
 
Glycolysis is a major metabolic pathway, which is of interest not only to people involved in the study of diabetes and metabolism in general, but also in the context of cancer and cell development. It is commonly thought that glycolysis has revealed all its secrets. This is not true.

Researchers reveal a basic mechanism that has never been suggested in the literature and that explains neutropenia in G6PC3 and G6PT deficiencies: the lack of dephosphorylation of a non-canonical metabolite, (1,5-anhydroglucitol-6-phosphate; 1,5AG6P) which can easily be made from a major polyol present in blood (1,5-anhydroglucitol), strongly impairs glucose metabolism in neutrophils. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with the findings, Prof. Van Schaftingen’s team observed that treatment with a 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. These mouse experiments now provide the ground for a proof of concept human study in G6PC3 deficient and GSD 1b patients using an SGLT2 inhibitor to lower blood 1,5-anhydroglucitol.
 
When trying to understand many of the still mysterious Inborn Errors of Metabolism, it is important to be aware that quite a few enzymes in our cells act on substrates that resemble, but are not identical, to their physiological substrate, thereby leading to non-canonical, sometimes toxic metabolites. This study highlights the essential role played by metabolite repair enzymes to maintain normal metabolic functions. It also demonstrates that the search for metabolite repair enzymes can lead to explanations for diseases that have remained until now completely mysterious. It is very likely that other diseases will reveal one day to be due to a defect in an as yet unknown metabolite repair process.
 
190114 Van Schaftingen PNASIllu2 web
 
Illustration of the role played by 1,5-anhydroglucitol-6-phosphate accumulation in the neutropenia found in G6PC3 and G6PT deficiency. When patients are deficient in G6PT or G6PC3, 1,5AG6P accumulates in neutrophils to concentrations that strongly inhibit low-KM hexokinases, the enzymes catalyzing the first step of glycolysis. This depletes the intracellular pool of glucose-6-P in granulocytes, which likely decreases ATP production in glycolysis, as well as NADPH production in the pentose-P pathway and also UDP-glucose availability for protein glycosylation. This explains neutrophil dysfunction and neutropenia described in these patients.

Article references: Veiga-da-Cunha M, et al. (2019), Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency. PNAS. doi: 10.1073/pnas.1816143116

Dr Maria Veiga da Cunha has received for this work a Late Breaking News Award during the “Annual Conference of the Society for the Study of Inborn Errors of Metabolism (SSIEM) » which was held in Athens last year.

In a study led by Prof. Emile Van Schaftingen (WELBIO investigator at Université Catholique de Louvain), scientists showed that 2 rare genetic diseases leading to an abnormally low concentration of neutrophils  in the blood (neutropenia) are due to a lack of metabolic repair which causes the accumulation of a toxic product. The results of this study have been published in PNAS.


Last update : 15/1/2019 - Vie privée - Printable version -  © 2019 WELBIO

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