A major interest of our group has been the elucidation of the mechanism by which a deficiency of the glucose-6-phosphate transporter of the endoplasmic reticulum (glycogen storage disease type Ib) or in G6PC3, a phosphatase present in the endoplasmic reticulum cause a neutropenia and severe infections in patients. After several years of work, we came to the conclusion that both proteins collaborate to hydrolyse 1,5-anhydroglucitol-6-phosphate, a glucose-6-phosphate analogue known to be a potent inhibitor of hexokinases.
This non classical intermediate is formed by side activities of glucose-phosphorylating enzymes on a polyol, 1,5-anhydroglucitol, that is naturally present in the blood at a concentration of ≈ 0.15 mM. When either G6PC3 or the glucose-6-phosphate transporter are deficient 1,5-anhydroglucitol-6-phosphate accumulates, particularly in the neutrophils, which are cells that are heavily dependent on glucose metabolism and are therefore particularly affected by either of these deficiencies.
But there is a way out: SGLT2 inhibitors, which are used in the treatment of diabetes to enhance urinary excretion of glucose, also cause the elimination of 1,5-anhydroglucitol, whose concentration decreases in blood. These drugs are therefore now used to treat successfully the neutropenia in G6PC3 deficiency and in glycogen storage disease type Ib.
We are also interested in enzymes catalysing the synthesis of metabolites whose function is still not really understood. One example is glucose-1,6-bisphosphate, a well-known cofactor of phosphoglucomutase, but which is present in some tissues like the brain at concentrations that are more than 100 fold higher than what is needed for the function of phosphoglucomutase. More than ten years ago, we have identified the gene encoding the enzyme that synthesizes glucose-1,6-phosphate in the brain. In collaboration with clinicians, we have more recently described a new neurological disease due to a defect in this enzyme. Obviously, glucose-1,6-bisphosphate must play an important role in the brain. We aim at understanding this role.