Figures & data
Figure 1. Phosphorylated intermediates regulate both metabolic flux by feedforward allosteric activation and intracellular homeostasis by feedback repression of the glucokinase gene. At basal glucose (∼ 5 mM) GK is sequestered in the nucleus bound to GKRP in its open inactive state. An increase in blood glucose and also GKAs release glucokinase from GKRP causing its translocation to the cytoplasm, stimulation of glucose phosphorylation and an increase in cell. Cytoplasmic G6P concentration correlates directly with GK activity and inversely with the activity of G6pc which is located in the ER. (1) Glucokinase interacts with PFKFB2 forming F26P2, which allosterically activates PFK1and its product allosterically activates Pklr resulting in feedforward activation of glycolysis, which generates substrate for lipogenesis. (2) Raised levels of F26P2 also cause translocation of Mlx-linked transcription factors (e.g., ChREBP) to the nucleus and recruitment to gene promoters causing induction of G6pc, Pklr and lipogenic enzymes (e.g., Fasn) and repression of the Gck gene Citation[14,15]. The proteins encoded by these genes have long half-lives Citation[14] and changes in protein expression manifest with a much slower time course than allosteric mechanisms. Because GKAs have opposite effects on glucokinase activity (rapid activation and slow Gck gene repression), a net decline in glucokinase activity would manifest when acute activation can no longer compensate for the decline in protein expression.
![Figure 1. Phosphorylated intermediates regulate both metabolic flux by feedforward allosteric activation and intracellular homeostasis by feedback repression of the glucokinase gene. At basal glucose (∼ 5 mM) GK is sequestered in the nucleus bound to GKRP in its open inactive state. An increase in blood glucose and also GKAs release glucokinase from GKRP causing its translocation to the cytoplasm, stimulation of glucose phosphorylation and an increase in cell. Cytoplasmic G6P concentration correlates directly with GK activity and inversely with the activity of G6pc which is located in the ER. (1) Glucokinase interacts with PFKFB2 forming F26P2, which allosterically activates PFK1and its product allosterically activates Pklr resulting in feedforward activation of glycolysis, which generates substrate for lipogenesis. (2) Raised levels of F26P2 also cause translocation of Mlx-linked transcription factors (e.g., ChREBP) to the nucleus and recruitment to gene promoters causing induction of G6pc, Pklr and lipogenic enzymes (e.g., Fasn) and repression of the Gck gene Citation[14,15]. The proteins encoded by these genes have long half-lives Citation[14] and changes in protein expression manifest with a much slower time course than allosteric mechanisms. Because GKAs have opposite effects on glucokinase activity (rapid activation and slow Gck gene repression), a net decline in glucokinase activity would manifest when acute activation can no longer compensate for the decline in protein expression.](/cms/asset/aabc6278-a81a-40b5-be33-a82c64aa5a6f/ietp_a_965680_f0001_b.jpg)