Glycogen synthase

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Glycogen synthase kinase-3 GSK3 may be the busiest kinase in most cells, with over known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others.

Glycogen synthase

Federal government websites often end in. The site is secure. Glycogen synthase kinase 3 GSK3 , a constitutively acting multi-functional serine threonine kinase is involved in diverse physiological pathways ranging from metabolism, cell cycle, gene expression, development and oncogenesis to neuroprotection. GSK3 has been implicated in various diseases such as diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. Consequently, inhibitors of GSK3 have been demonstrated to have anti-diabetic effects in vitro and in animal models. However, inhibition of GSK3 poses a challenge as achieving selectivity of an over achieving kinase involved in various pathways with multiple substrates may lead to side effects and toxicity. The primary concern is developing inhibitors of GSK3 that are anti-diabetic but do not lead to up-regulation of oncogenes. The focus of this review is the recent advances and the challenges surrounding GSK3 as an anti-diabetic therapeutic target. British Journal of Pharmacology doi The name glycogen synthase kinase does not adequately describe the multitude of diverse substrates and functions attributed to GSK3. It is involved in a variety of cellular processes ranging from glycogen metabolism, insulin signalling, cell proliferation, neuronal function, oncogenesis to embryonic development. Of the many diverse substrates, some of the key molecules mediating GSK3 functions in regulation of several cellular processes are glycogen synthase GS , tau protein and beta catenin proteins Eldar-Finkelman, ; Jope and Johnson,

About this article. GSK3 inhibitors could also have a beneficial effect for type I diabetes and also islet transplantation patients.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Glycogen is the major glucose reserve in eukaryotes, and defects in glycogen metabolism and structure lead to disease.

Although glucose is the primary fuel for cells, it is not an efficient molecule for long-term storage in complex i. Therefore, in both plants and animals, the glucose molecules are linked together to form polysaccharides known as glucans. The average size of a glycogen unit is a cytoplasmic granule containing over glucose molecules. The addition of a glucosephosphate to another or to a glycogen chain is energetically unfavorable, so it must be coupled with a sufficiently exergonic reaction to proceed. The phosphoanhydride exchange reaction catalyzed by UDP-glucose phosphorylase is minimally exergonic. However, the pyrophosphate released is quickly hydrolyzed by inorganic pyrophosphatase, a ubiquitous cytosolic enzyme, in a highly exergonic reaction. This pyrophosphate hydrolysis is a mechanism utilized in many biosynthetic pathways to provide energy for otherwise endergonic reactions. It cannot join two individual glucoses together, only add to a pre-existing chain. This means that there must be some workaround for the first two glucoses: glycogenin is an enzyme that catalyzes the addition of UDP-glucose to itself, and can do so for up to seven UDP-glucose molecules, thus forming a short primer for glycogen synthase to work with. This enzyme can transfer terminal chain segments to the 6-carbon hydroxyl of any glucose in a glycogen chain.

Glycogen synthase

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GSK3 negatively regulates insulin-mediated glycogen synthesis and glucose homeostasis, and increased expression and activity of GSK3 has been reported in type II diabetics and obese animal models. MolProbity: all-atom structure validation for macromolecular crystallography. Chronic selective glycogen synthase kinase-3 inhibition enhances glucose disposal and muscle insulin action in prediabetic obese Zucker rats. Article Talk. GS is inactivated by covalent phosphorylation at numerous N- and C-terminal sites Fig. Rohou, A. Bioorg Med Chem. The distances between Cys and Cys 3. Thus, we see no evidence to support the hypothesis that the phosphorylated tails interact with residues lining the G6P pocket to directly compete with G6P binding. This UDP-glc-bound R state is predicted to be the catalytic competent state, which is poised for binding to the glucose chain substrate 29 , The percentage of particles contributing to each peak is shown in brackets.

Glycogen synthase UDP-glucose-glycogen glucosyltransferase is a key enzyme in glycogenesis , the conversion of glucose into glycogen. It is a glycosyltransferase EC 2. Much research has been done on glycogen degradation through studying the structure and function of glycogen phosphorylase , the key regulatory enzyme of glycogen degradation.

Challenges and opportunities with glycogen synthase kinase-3 inhibitors for insulin resistance and Type 2 diabetes treatment. Insulin mediates most of its actions through IRS1 and IRS2 that recruit src homology 2 proteins such as p85 regulatory subunit of phosphoinositol 3 kinase, src homology protein tyrosine phosphatase 2, growth factor receptor bound protein 2 Eldar-Finkelman and Krebs, Glucosephosphate G6P is from Roche. Data are representative of three independent experiments. Fifty frames over 3. Christopher Browning, Sarah C. A unique feature of metazoan GS is that both N- and C-terminal tails are phosphorylated, but the mechanism by which they participate in enzyme inactivation has remained elusive. Daly, L. EMBO J. Increase in IRS1 protein expression in skeletal muscle could augment insulin action. The dried filters were subjected to scintillation counting. To gain a higher resolution structure for the human GS, we applied D2 symmetry and achieved a global resolution of 2. Cells 7 , 87—17