Glucose-6-phosphatase catalytic subunit alpha (G6PC) (G6PC)

Glucose-6-phosphatase catalytic subunit alpha (G6PC) is a critical enzyme located in the endoplasmic reticulum membrane, primarily expressed in the liver, kidneys, and intestinal mucosa [1, 3]. It catalyzes the final step of both gluconeogenesis and glycogenolysis by hydrolyzing glucose-6-phosphate into free glucose and inorganic phosphate, a process essential for maintaining blood glucose levels during fasting [1, 5]. Genetic mutations in the G6PC gene lead to Glycogen Storage Disease Type Ia (GSD Ia), also known as von Gierke disease, which is characterized by life-threatening fasting hypoglycemia, hepatomegaly, and severe metabolic derangements [7, 14]. Conversely, the overactivity or overexpression of G6PC is associated with increased hepatic glucose production in Type 2 diabetes and metabolic syndrome [13, 15]. Therapeutic strategies currently under development include gene therapies like DTX401 (pariglasgene brecaparvovec), which aim to restore endogenous enzyme activity in GSD Ia patients to reduce their dependence on dietary glucose supplements [6, 8]. Additionally, small-molecule inhibitors are being explored for their potential to manage hyperglycemia by modulating hepatic glucose output, although achieving precise control without inducing hypoglycemia remains a significant clinical challenge [13, 16].

Other names

G6PaseG6PC1G6Pase-alphaG-6-PaseGlucose-6-phosphatase alphaGSD1aGlucose-6-phosphatase catalytic subunit 1

Gene replacement therapy, mRNA-mediated enzyme expression, competitive enzyme inhibition, and base editing for genetic correction.