Glucose-6-Phosphatase Structure, Regulation, and Function: An Update

Abstract

Work on the glucose-6-phosphatase system has intensified and diversified extensively in the past 3 years. The gene for the catalytic unit of the liver enzyme has been cloned from three species, and regulation at the level of gene expression is being studied in several laboratories worldwide. More than 20 sites of mutation in the catalytic unit protein have been demonstrated to underlie glycogenesis type 1a. inhibition of glucose-6-P hydrolysis by several newly identified competitive and time-dependent, irreversible inhibitors has been demonstrated and in several instances the predicted effects on liver glycogen formation and/or breakdown and on blood glucose production have been shown. Refinements in and additions to the presently dominant "substrate transport-catalytic unit" topological model for the glucose-6-phosphatase system have been made. A new model alternative to this, based on the "combined conformational flexibility-substrate transport" concept, has emerged. Experimental evidence for the phosphorylation of glucose in liver by high-K(m),glucose enzyme(s) in addition to glucokinase has continued to emerge, and new in vitro evidence supportive of biosynthetic functions of the glucose-6-phosphatase system in this role has appeared. High levels of multifunctional glucose-6-phosphatase have been shown present in pancreatic islet beta cells. Glucose-6-P has been established as the likely insulin secretagog in beta cells. Interesting differences in the temporal responses of glucose-6-phosphatase in kidney and liver have been demonstrated. An initial attempt is made here to meld the hepatic and pancreatic islet beta-cell glucose-6-phosphatase systems, and to a lesser extent the kidney tubular and small intestinal mucosal glucose-6-phosphatase systems into an integrated, coordinated mechanism involved in whole-body glucose homeostasis in health and disease.

Protein Kinase A Phosphorylates Hepatocyte Nuclear Factor-6 and Stimulates Glucose-6-phosphatase Catalytic Subunit Gene Transcription

“…In this model the other components of the glucose-6-phosphatase system act as transport proteins to shuttle both substrate and product across the endoplasmic reticulum membrane (1,2). These include a glucose-6-phosphate transporter and putative transporters for inorganic phosphate and glucose (1,2). Inactivating mutations in the G6Pase and glucose-6-phosphate transporter genes gives rise to glycogen storage disease types 1a and 1b, respectively (4).…”

“…One model has been proposed in which, in adults, in contrast to the fetus (3), the active site of the catalytic subunit of glucose-6-phosphatase (G6Pase) 1 is contained within the lumen of the endoplasmic reticulum (1,2). In this model the other components of the glucose-6-phosphatase system act as transport proteins to shuttle both substrate and product across the endoplasmic reticulum membrane (1,2). These include a glucose-6-phosphate transporter and putative transporters for inorganic phosphate and glucose (1,2).…”

“…Glucose-6-phosphatase is a multicomponent system located in the endoplasmic reticulum that catalyzes the terminal step in gluconeogenesis and hepatic glycogenolysis (1,2). The kinetics of glucose-6-phosphate hydrolysis by glucose-6-phosphatase are complex, and several models for the glucose-6-phosphatase system have been proposed (1,2).…”

“…The kinetics of glucose-6-phosphate hydrolysis by glucose-6-phosphatase are complex, and several models for the glucose-6-phosphatase system have been proposed (1,2). One model has been proposed in which, in adults, in contrast to the fetus (3), the active site of the catalytic subunit of glucose-6-phosphatase (G6Pase) 1 is contained within the lumen of the endoplasmic reticulum (1,2). In this model the other components of the glucose-6-phosphatase system act as transport proteins to shuttle both substrate and product across the endoplasmic reticulum membrane (1,2).…”

Identification of protein components of the microsomal glucose 6-phosphate transporter by photoaffinity labelling

“…In mammals the liver is the organ responsible for the homoeostatic regulation of blood glucose levels [1][2][3]. Glucose-6-phosphatase (EC 3.1.3.9) catalyses the terminal step of hepatic glucose production by the hydrolysis of glucose 6-phosphate deriving from either gluconeogenesis or glycogenolysis in the endoplasmic reticulum of hepatocytes [1].…”