New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system

Eur J Biochem. 2000 Mar;267(6):1533-49. doi: 10.1046/j.1432-1327.2000.01160.x.

Abstract

The operation of glucose 6-phosphatase (EC 3.1.3.9) (Glc6Pase) stems from the interaction of at least two highly hydrophobic proteins embedded in the ER membrane, a heavily glycosylated catalytic subunit of m 36 kDa (P36) and a 46-kDa putative glucose 6-phosphate (Glc6P) translocase (P46). Topology studies of P36 and P46 predict, respectively, nine and ten transmembrane domains with the N-terminal end of P36 oriented towards the lumen of the ER and both termini of P46 oriented towards the cytoplasm. P36 gene expression is increased by glucose, fructose 2,6-bisphosphate (Fru-2,6-P2) and free fatty acids, as well as by glucocorticoids and cyclic AMP; the latter are counteracted by insulin. P46 gene expression is affected by glucose, insulin and cyclic AMP in a manner similar to P36. Accordingly, several response elements for glucocorticoids, cyclic AMP and insulin regulated by hepatocyte nuclear factors were found in the Glc6Pase promoter. Mutations in P36 and P46 lead to glycogen storage disease (GSD) type-1a and type-1 non a (formerly 1b and 1c), respectively. Adenovirus-mediated overexpression of P36 in hepatocytes and in vivo impairs glycogen metabolism and glycolysis and increases glucose production; P36 overexpression in INS-1 cells results in decreased glycolysis and glucose-induced insulin secretion. The nature of the interaction between P36 and P46 in controling Glc6Pase activity remains to be defined. The latter might also have functions other than Glc6P transport that are related to Glc6P metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adenoviridae / genetics
  • Amino Acid Sequence
  • Animals
  • Antiporters
  • Bacterial Proteins / physiology
  • Biological Transport
  • Carrier Proteins / physiology
  • Cyclic AMP / pharmacology
  • Cyclic AMP / physiology
  • Endoplasmic Reticulum / enzymology
  • Enzyme Induction / drug effects
  • Escherichia coli Proteins*
  • Fatty Acids, Nonesterified / metabolism
  • Fatty Acids, Nonesterified / pharmacology
  • Fructosediphosphates / metabolism
  • Fructosediphosphates / pharmacology
  • Gene Expression Regulation
  • Genetic Engineering
  • Genetic Vectors / genetics
  • Glucocorticoids / pharmacology
  • Glucocorticoids / physiology
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Glucose / physiology
  • Glucose-6-Phosphatase / chemistry
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / physiology*
  • Glycogen Storage Disease Type I / classification
  • Glycogen Storage Disease Type I / enzymology
  • Glycogen Storage Disease Type I / genetics
  • Glycogen Storage Disease Type I / metabolism
  • Glycolysis
  • Humans
  • Hydrolysis
  • Insulin / pharmacology
  • Insulin / physiology
  • Liver / metabolism
  • Macromolecular Substances
  • Microsomes / enzymology
  • Models, Molecular
  • Molecular Sequence Data
  • Monosaccharide Transport Proteins*
  • Phosphotransferases / chemistry
  • Phosphotransferases / genetics
  • Phosphotransferases / physiology
  • Second Messenger Systems
  • Structure-Activity Relationship

Substances

  • Antiporters
  • Bacterial Proteins
  • Carrier Proteins
  • Escherichia coli Proteins
  • Fatty Acids, Nonesterified
  • Fructosediphosphates
  • Glucocorticoids
  • Insulin
  • Macromolecular Substances
  • Monosaccharide Transport Proteins
  • SLC37A4 protein, human
  • UhpT protein, E coli
  • glucose 6-phosphate(transporter)
  • fructose 2,6-diphosphate
  • Cyclic AMP
  • Phosphotransferases
  • Glucose-6-Phosphatase
  • Glucose