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

Abstract

SignificanceNeutropenia 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 (1,5-anhydroglucitol-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 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. Our findings highlight that the elimination of noncanonical side products by metabolite-repair enzymes makes an important contribution to mammalian physiology.

Inborn errors of metabolite repair

“…On the contrary, administration of 1,5‐anhydroglucitol to G6PC3‐deficient mice further decreases their neutrophil count. Neutrophils isolated from patients with G6PC3 or G6PT deficiency, show concentrations of 1,5‐anhydroglucitol‐6‐phosphate (≈ 3 mM) that are far above the Ki of hexokinase 3 (the main hexokinase in neutrophils) for this inhibitor, and close to 1000‐fold higher than the concentration found in neutrophils from healthy controls …”

“…Identifying the toxic compound may be very difficult in the absence of ad hoc hypotheses, particularly if this compound is an unknown metabolite. Yet, identifying the exact function of a metabolite repair enzyme in the context of human inborn errors of metabolism may be very useful as it may lead to new therapeutic strategies, as appears to be the case for 1,5‐anhydroglucitol‐6‐phosphate …”

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

“…Neutrophils have been traditionally considered to selectively utilize glycolysis for energy metabolism due to having only a few mitochondria [179]. Extrinsic glucose is taken up into human neutrophils via GLUT1, which is expressed and upregulated in glucose-rich environments [180]. Patients with genetic deficiency in enzymes related to glucose metabolism suffer from neutrophil dysfunctions and neutropenia [20,27,180,181].…”

“…Extrinsic glucose is taken up into human neutrophils via GLUT1, which is expressed and upregulated in glucose-rich environments [180]. Patients with genetic deficiency in enzymes related to glucose metabolism suffer from neutrophil dysfunctions and neutropenia [20,27,180,181]. Neutrophils from glycogen storage disease (GSD) patients having glucose-6-phosphate transporter (G6PT) deficiency and manifest dysregulated function of energy homeostasis, ROS production, and chemotaxis, suggesting the importance of glucose metabolism in neutrophils [27].…”

Enzyme promiscuity, metabolite damage, and metabolite damage control systems of the tricarboxylic acid cycle

“…Enzymes can also occasionally catalyze an unintended reaction on a physiological substrate (i.e., catalytic promiscuity) [6,7]. Both substrate and catalytic promiscuities result in the formation of ‘unintended’, ‘noncanonical’, or ‘damaged’ metabolites (i.e., metabolite damage) that can be a useless drain on metabolism [8] and may be inhibitory [9], and/or reactive [10,11], sometimes leading to toxicity. In addition to enzyme promiscuity, spontaneous chemical reactions can occur to cellular metabolites causing metabolite damage [12].…”