glucose6phosphatase

Glucose-6-phosphatase, also known as glucose-6-phosphatase (G6Pase), is a microsomal enzyme that hydrolyzes glucose-6-phosphate to glucose and inorganic phosphate. It plays a crucial role in regulating blood glucose levels during fasting by enabling the final step of gluconeogenesis and glycogenolysis, primarily in liver and, to a lesser extent, kidney and intestinal tissues. The enzyme contributes to the release of free glucose into the bloodstream.

The activity of glucose-6-phosphatase depends on a coordinated system within the endoplasmic reticulum. The catalytic subunit, G6PC, resides in the ER membrane with its active site oriented toward the lumen, where hydrolysis occurs. Substrate delivery requires a glucose-6-phosphate transporter (G6PT, encoded by SLC37A4) that transports glucose-6-phosphate into the ER lumen. After hydrolysis, glucose must exit to the cytosol and then to the bloodstream. In mammals, several G6PC isoforms exist, including G6PC1 in liver, kidney, and intestine; G6PC2 in pancreatic beta cells, implicated in glucose sensing; and G6PC3, which is more widely expressed.

Genetic deficiencies of glucose-6-phosphatase disrupt glucose release and lead to glycogen storage diseases. Deficiency of G6PC causes glycogen storage disease type I (von Gierke disease), characterized by severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia, and growth retardation. Defects in G6PT (SLC37A4) cause glycogen storage disease type Ib, which includes neutropenia and increased susceptibility to infections. Management of GSD I typically involves dietary strategies, such as regular administration of slow- or uncooked cornstarch to maintain normoglycemia, along with other supportive measures; research into therapies continues.