Article (Scientific journals)
Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency
Veiga-da-Cunha, Maria; Chevalier, Nathalie; Stephenne, Xavier et al.
2019In Proceedings of the National Academy of Sciences of the United States of America, 116 (4), p. 1241-1250
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Keywords :
neutropenia; SLGT2 inhibitors; 1,5-anhydroglucitol; metabolite repair; glucose-6-phosphatase-β
Abstract :
[en] Neutropenia presents an important clinical problem in patients with G6PC3 or G6PT deficiency, yet why neutropenia occurs is unclear. We discovered that G6PC3 and G6PT collaborate to dephosphorylate a noncanonical metabolite (1,5anhydroglucitol-6-phosphate; 1,5AG6P) which is produced when glucose-phosphorylating enzymes erroneously act on 1,5-anhydroglucitol, a food-derived polyol present in blood. 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 our findings, we observed that treatment with a 1,5anhydroglucitol-lowering drug treats neutropenia in G6PC3deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology.
Disciplines :
Endocrinology, metabolism & nutrition
Biochemistry, biophysics & molecular biology
Author, co-author :
Veiga-da-Cunha, Maria
Chevalier, Nathalie
Stephenne, Xavier
Defour, Jean-Philippe
Paczia, Nicole ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Ferster, Alina
Achouri, Younes
Dewulf, Joseph P
Linster, Carole  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Bommer, Guido T
Van Schaftingen, Emile
External co-authors :
yes
Language :
English
Title :
Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency
Publication date :
22 January 2019
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington DC, United States - District of Columbia
Volume :
116
Issue :
4
Pages :
1241-1250
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 14 January 2019

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