G6Pases

G6Pases are a family of enzymes that catalyze the hydrolysis of glucose-6-phosphate to produce free glucose and inorganic phosphate. The most common member is glucose‑6‑phosphatase (G6PC), which is primarily expressed in liver, kidney, and small intestinal enterocytes. Another related protein, G6PC3, is found in many tissues and has distinct regulatory properties. These enzymes are integral components of the hepatic gluconeogenesis and glycogenolysis pathways, allowing the organism to release glucose into the bloodstream during fasting or increased energy demand.

Structurally, G6Pases are membrane proteins situated in the endoplasmic reticulum. Their catalytic site resides in the lumen, where glucose‑6‑phosphate is transported into the ER via specific translocator proteins (G6PT). After hydrolysis by G6PC, the resulting glucose diffuses out of the cell, contributing to blood glucose maintenance. In kidneys and enterocytes, analogous mechanisms facilitate glucose recycling and absorption.

Clinical significance arises when mutations disrupt G6Pase activity. Loss‑of‑function variants in G6PC cause glycogen storage disease type Ia, characterized by hypoglycemia, hepatomegaly, and lactic acidosis. Defects in G6PC3 are associated with a broader spectrum of symptoms, including leukopenia, chronic infections, and thrombosis, reflecting its more widespread tissue expression. Therapeutic approaches focus on dietary glucose supplementation, anti‑glycogenolytic agents, and, in research settings, gene therapy vectors aimed at restoring enzyme activity.

Research on G6Pases continues to illuminate their role in metabolic regulation, expanding understanding of glucose homeostasis and offering potential targets for metabolic and infectious disease intervention.