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Molecular Coordination of Hepatic Glucose Metabolism by the 6-Phosphofructo-2-Kinase/Fructose-2,6- Bisphosphatase:Glucokinase Complex

Department of Veterans Affairs Medical Center (W.E.S., D.A.O.), Minneapolis, Minnesota 55417; Institute of Clinical Biochemistry (S.L., S.B.), Hannover Medical School, 30623 Hannover, Germany; and Department of Biochemistry (C.W.), Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: David A. Okar, Ph.D., Veterans Affairs Medical Center, Minneapolis, 1 Veterans Drive, Room 3P-105, Minneapolis, Minnesota 55417. E-mail: David.Okar{at}med.va.gov.

Glucokinase (GK) and 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase (FBP-2) are each powerful regulators of hepatic carbohydrate metabolism that have been reported to influence each other’s expression, activities, and cellular location. Here we present the first physical evidence for saturable and reversible binding of GK to the FBP-2 domain of PFK-2/FBP-2 in a 1:1 stoichiometric complex. We confirmed complex formation and stoichiometry by independent methods including affinity resin pull-down assays and fluorescent resonance energy transfer. All suggest that the binding of GK to PFK-2/FBP-2 is weak. Enzymatic assays of the GK:PFK-2/FBP-2 complex suggest a concomitant increase of the kinase-to-bisphosphatase ratio of bifunctional enzyme and activation of GK upon binding. The kinase-to-bisphosphatase ratio is increased by activation of the PFK-2 activity whereas FBP-2 activity is unchanged. This means that the GK-bound PFK-2/FBP-2 produces more of the biofactor fructose-2,6-bisphosphate, a potent activator of 6-phosphofructo-1-kinase, the committing step to glycolysis. Therefore, we conclude that the binding of GK to PFK-2/FBP-2 promotes a coordinated up-regulation of glucose phosphorylation and glycolysis in the liver, i.e. hepatic glucose disposal. The GK:PFK-2/FBP-2 interaction may also serve as a metabolic signal transduction pathway for the glucose sensor, GK, in the liver. Demonstration of molecular coordination of hepatic carbohydrate metabolism has fundamental relevance to understanding the function of the liver in maintaining fuel homeostasis, particularly in managing excursions in glycemia produced by meal consumption.

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