Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity

Abstract

Glucokinase (GK), mainly expressed in the liver and pancreatic β-cells, is critical for maintaining glucose homeostasis. GK expression and kinase activity, respectively, are both modulated at the transcriptional and post-translational levels. Post-translationally, GK is regulated by binding the glucokinase regulatory protein (GKRP), resulting in GK retention in the nucleus and its inability to participate in cytosolic glycolysis. Although hepatic GKRP is known to be regulated by allosteric mechanisms, the precise details of modulation of GKRP activity, by post-translational modification, are not well known. Here, we demonstrate that GKRP is acetylated at Lys5 by the acetyltransferase p300. Acetylated GKRP is resistant to degradation by the ubiquitin-dependent proteasome pathway, suggesting that acetylation increases GKRP stability and binding to GK, further inhibiting GK nuclear export. Deacetylation of GKRP is effected by the NAD+-dependent, class III histone deacetylase SIRT2, which is inhibited by nicotinamide. Moreover, the livers of db/db obese, diabetic mice also show elevated GKRP acetylation, suggesting a broader, critical role in regulating blood glucose. Given that acetylated GKRP may affiliate with type-2 diabetes mellitus (T2DM), understanding the mechanism of GKRP acetylation in the liver could reveal novel targets within the GK-GKRP pathway, for treating T2DM and other metabolic pathologies.

Who watches the watchmen? Regulation of the expression and activity of sirtuins

“…Similar to several other sirtuins, SIRT2 is involved in energy homeostasis (126). For instance, it deacetylates glucokinase (GK) (127) and phosphoenolpyruvate carboxykinase (PEPCK) (128), destabilizing the former but stabilizing the latter. GK facilitates glucose phosphorylation, the first step leading to glycolysis and glycogenesis, and PEPCK is a rate‐limiting enzyme of gluconeogenesis.…”

Quantitative proteomics reveals decreased expression of major urinary proteins in the liver of apoE/eNOS‐DKO mice

“…GKRP is responsible for the regulation of hepatic glucose metabolism by controlling an activity and cellular localization of glucokinase – an enzyme that phosphorylates glucose, preparing it for glycogen synthesis or glycolysis . It has been demonstrated that polymorphism or acetylation of GKRP were associated with type 2 diabetes . Similarly, the diminished expression of GYS2 – a protein engaged in glycogen biosynthesis – was observed in patients with type 2 diabetes .…”

Associations between glucokinase and glucokinase regulatory protein gene polymorphisms and clinical parameters in pregnant women

“…In the liver, GCKR forms an inhibitory complex with GCK, the enzyme responsible for regulating the uptake and storage of dietary glucose [15]. The glucokinase Associations between glucokinase and glucokinase regulatory protein gene polymorphisms and clinical parameters in pregnant women regulatory protein regulates hepatic GCK activity competitively with respect to the substrate glucose, the phosphate esters fructose 6-and fructose 1-phosphate, which enhance or inhibit the action of the regulatory protein, respectively [16,17].…”