It was known in the 1950s that hepatic microsomal
glucose-6-phosphatase plays an important role in the regulation of
blood glucose levels. All attempts since then to purify a single
polypeptide with
glucose-6-phosphatase activity have failed. Until recently, virtually nothing was known about the molecular basis of
glucose-6-phosphatase or its regulation. Recent studies of the type 1
glycogen storage diseases, which are human genetic deficiencies that result in impaired
glucose-6-phosphatase activity, have greatly increased our understanding of
glucose-6-phosphatase.
Glucose-6-phosphatase has been shown to comprise at least five different
polypeptides, the catalytic subunit of
glucose-6-phosphatase with its active site situated in the lumen of the endoplasmic reticulum; a regulatory Ca2+
binding protein; and three
transport proteins, T1, T2, and T3, which respectively allow
glucose-6-phosphate,
phosphate, and
glucose to cross the endoplasmic reticulum membrane. Purified
glucose-6-phosphatase proteins, immunospecific
antibodies, and improved assay techniques have led to the diagnosis of a variety of new type 1
glycogen storage diseases. Recent studies of the type 1
glycogen storage diseases have led to a much greater understanding of the role and regulation of each of the
glucose-6-phosphatase proteins.