Glucose 6-phosphatase

Enzyme

The enzyme glucose 6 phosphatase (EC 3.1.3.9, G6Pase; systematic name D glucose 6 phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6 phosphate, resulting in the creation of a phosphate group and free glucose:

D glucose 6 phosphate + H2O = D glucose + phosphate

Glucose is then exported from the cell via glucose transporter membrane proteins. This catalysis completes the final step in gluconeogenesis and therefore plays a key role in the homeostatic regulation of blood glucose levels. Glucose 6 phosphatase is a complex of multiple component proteins, including transporters for G6P, glucose, and phosphate. The main phosphatase function is performed by the glucose 6 phosphatase catalytic subunit. In humans, there are three isozymes of the catalytic subunit: glucose 6 phosphatase α, encoded by G6PC; IGRP, encoded by G6PC2; and glucose 6 phosphatase β, encoded by G6PC3. Glucose 6 phosphatase α and glucose 6 phosphatase β are both functional phosphohydrolases, and have similar active site structure, topology, mechanism of action, and kinetic properties with respect to G6P hydrolysis. In contrast, IGRP has almost no hydrolase activity, and may play a different role in stimulating pancreatic insulin secretion.

Although a clear consensus has not been reached, a large number of scientists adhere to a substrate transport model to account for the catalytic properties of glucose 6 phosphatase. In this model, glucose 6 phosphatase has a low degree of selectivity. The transfer of the glucose 6 phosphate is carried out by a transporter protein (T1) and the endoplasmic reticulum (ER) contains structures allowing the exit of the phosphate group (T2) and glucose (T3). Glucose 6 phosphatase consists of 357 amino acids, and is anchored to the endoplasmic reticulum (ER) by nine transmembrane helices. Its N terminal and active site are found on the lumen side of the ER and its C terminus projects into the cytoplasm. Due to its tight association to the ER, the exact structure of glucose 6 phosphatase remains unknown. However, sequence alignment has shown that glucose 6 phosphatase is structurally similar to the active site of the vanadium containing chloroperoxidase found in Curvularia inaequalis. Based on pH kinetic studies of glucose 6 phosphatase α catalysis, it was proposed that the hydrolysis of glucose 6 phosphate was completed via a covalent phosphohistidine glucose 6 phosphate intermediate. The active site of glucose 6 phosphatase α was initially identified by the presence of a conserved phosphate signature motif usually found in lipid phosphatases, acid phosphatases, and vanadium haloperoxidases. Thus, the glycogen that muscles store is not usually available for the rest of the body's cells because glucose 6 phosphate cannot cross the sarcolemma unless it is dephosphorylated. The enzyme plays an important role during periods of fasting and when glucose levels are low. It has been shown that starvation and diabetes induces a two to threefold increase in glucose 6 phosphatase activity in the liver.

Mutations of the glucose 6 phosphatase system, to be specific the glucose 6 phosphatase α subunit (glucose 6 phosphatase α), glucose 6 transporter (G6PT), and glucose 6 phosphatase β (glucose 6 phosphatase β or G6PC3) subunits lead to deficiencies in the maintenance of interprandial glucose homeostasis and neutrophil function and homeostasis. Mutations in both glucose 6 phosphatase α and G6PT lead to glycogen storage disease type I (GSD 1, von Gierke's disease). To be specific, mutations in the glucose 6 phosphatase α lead to Glycogen Storage Disease Type 1a, which is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. GSD 1a constitutes approximately 80% of GSD 1 cases that present clinically. Absence of G6PT leads to GSD 1b (GSD 1b), which is characterized by the lack of a G6PT and represents 20% of the cases that present clinically. The specific cause of the GSD 1a stems from nonsense mutations, insertions/deletions with or without a shift in the reading frame, or splice site mutations that occur at the genetic level. It can also lead to cardiac and urogenital malformations. This third class of deficiency is also affected by a G6PT deficiency as glucose 6 phosphatase β also lies within the ER lumen and thus can lead to similar symptoms of glucose 6 phosphatase β deficiency be associated with GSD 1b. The neutrophil glycosylation has a profound effect on neutrophil activity and thus may also be classified as a congenital glycosylation disorder as well.