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Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1241-1250. doi: 10.1073/pnas.1816143116. Epub 2019 Jan 9.

Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency.

Author information

1
Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium; maria.veiga@uclouvain.be emile.vanschaftingen@uclouvain.be.
2
Groupe de Recherches Metaboliques, de Duve Institute, UCLouvain (Université Catholique de Louvain), B-1200 Brussels, Belgium.
3
Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.
4
Service de Gastro-Entérologie et Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium.
5
Biologie Hématologique, Cliniques Universitaires Saint-Luc, UCLouvain, B-1200 Brussels, Belgium.
6
Luxembourg Centre for Systems Biomedicine, Université du Luxembourg, L-4367 Belvaux, Luxembourg.
7
Department of Hematology/Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, B-1020 Brussels, Belgium.

Abstract

Neutropenia represents an important problem in patients with genetic deficiency in either the glucose-6-phosphate transporter of the endoplasmic reticulum (G6PT/SLC37A4) or G6PC3, an endoplasmic reticulum phosphatase homologous to glucose-6-phosphatase. While affected granulocytes show reduced glucose utilization, the underlying mechanism is unknown and causal therapies are lacking. Using a combination of enzymological, cell-culture, and in vivo approaches, we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-K M hexokinases, which catalyze the first step in glycolysis in most tissues. We show that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol, a compound normally present in human plasma, by side activities of ADP-glucokinase and low-K M hexokinases. Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (∼3 mM) that strongly inhibit hexokinase activity. In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death. Treating G6PC3-deficient mice with an inhibitor of the kidney glucose transporter SGLT2 to lower their blood level of 1,5-anhydroglucitol restored a normal neutrophil count, while administration of 1,5-anhydroglucitol had the opposite effect. In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.

KEYWORDS:

1,5-anhydroglucitol; SLGT2 inhibitors; glucose-6-phosphatase-β; metabolite repair; neutropenia

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