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    • An important difference between glucokinase and the other he

    2022-05-31

    An important difference between glucokinase and the other hexokinases is that it has a much lower affinity for glucose, such that it is not saturated at physiological blood glucose concentrations (Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). In addition, glucokinase is not inhibited by its product, glucose-6-phosphate (Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). These unique properties of glucokinase, compared to other vertebrate hexokinases, means that the activity of glucokinase varies with glucose concentrations, thus can act as a sensor of glucose levels (Wilson, 1995, Wilson, 1997, Wilson, 2003, Wilson, 2004, Cárdenas et al., 1998). Hexokinases I, II, and III likely function to immediately phosphorylate any glucose (or hexose sugar) that enters a cell, thus driving glucose metabolism and the survival of the cells. Glucokinase, in contrast, has been adapted for a regulatory role, where it can control physiological processes at the whole organism level. The changes in the sequences of glucokinase compared to hexokinases that account for these functional differences are currently unknown.
    Glucokinase regulatory protein and the tissue-specific roles of glucokinase While all hexokinases can phosphorylate glucose, glucokinase is the hexokinase with the most important role in glucose homeostasis in mammals. Glucokinase is expressed in tissues with essential roles in the regulation of blood glucose levels, and mutations in this gene, MODY2 mutations, lead to diabetes (Printz et al., 1993b, Iynedjian, 1993, Iynedjian, 2009). Glucokinase is expressed in the liver, pancreatic islets, and select ask1 inhibitor in the gut and the brain. In the liver glucokinase functions to regulate glucose metabolism, while in the pancreatic islets, intestinal cells and neurons it functions as a glucose sensor (Iynedjian, 1993, Iynedjian, 2009, Postic et al., 2001, Agius, 2008). As a key component of the glucose sensor in pancreatic islet beta-cells, glucokinase regulates the release on insulin in response to blood glucose levels (Postic et al., 2001, Agius, 2008). In intestinal and neuronal cells, glucokinase functions similarly to regulate responses of these tissues to changes in blood glucose levels (Iynedjian, 2009). To function as a glucose sensor, glucokinase must always be present in a cell, thus it can instantly respond to change in blood glucose levels. In the liver, in contrast, glucokinase must only function when blood glucose levels are elevated; therefore its activity in these cells is regulated, where this is achieved at both the transcriptional and post-transcriptional level (Iynedjian, 1993, Iynedjian, 2009). Tissue-specific expression of glucokinase is mediated though a pair of unique promoters, where an upstream promoter drives expression in pancreatic beta-cells as well as select gut and neuronal cells, and a downstream promoter drives expression in the liver (Magnuson et al., 1989, Tanizawa et al., 1992, Postic et al., 1995). Little, if any, transcriptional regulation occurs at the upstream promoter that functions in pancreatic islet, intestinal and neuronal cells, likely due to these cells requiring a constant presence of glucokinase for glucose sensing (Postic et al., 2001, Iynedjian, 2009). In contrast, the liver-specific promoter is transcriptionally regulated, yielding glucokinase activity when blood glucose levels are elevated (Postic et al., 2001, Iynedjian, 1993, Iynedjian, 2009). However, since changes in blood glucose levels can occur rapidly, at rates more rapid than can be addressed by transcriptional regulation, changes in glucokinase activity levels is also regulated at the post-translational level (van Schaftingen et al., 1997, Agius, 2008, Iynedjian, 2009). Post-translationally, glucokinase is regulated by an interaction with glucokinase regulatory protein (GCKR), where binding to GCKR results in the loss of enzymatic activity and localization to the nucleus, while active glucokinase is found in the cytoplasm and is not bound to GCKR (Agius and Peak, 1997, van Schaftingen et al., 1997). Levels of fructose-6-phosphate, which change in parallel with blood glucose levels, regulate the binding of glucokinase with GCKR, allowing glucokinase to be active only when blood glucose levels are elevated (Agius and Peak, 1997, van Schaftingen et al., 1997). GCKR is only abundantly expressed in the liver, and not appreciably in the other sites of glucokinase expression (Detheux et al., 1993, Vandercammen and Van Schaftingen, 1993). The tissue-specific expression of GCKR in the liver therefore permits glucokinase to be post-transcriptionally regulated only in the liver, the one tissue where activity must be regulated to prevent function when blood glucose levels are low.