Kinases glycogen synthase

Liver Activation of glycogen synthesis Activation of glycogen synthase (GS) Inactivation of glycogen synthase kinase 3 (GSK3) through phosphorylation by Akt... 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

Nserum L, Nprskov-Lauritsen L, Olesen PH. Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors. Bioorg Med Chem Lett 2002 12 1525-8. 

Figure 18-7. Control of glycogen synthase in muscle (n = number of glucose residues). The sequence of reactions arranged in a cascade causes amplification at each step, allowing only nanomole quantities of hormone to cause major changes in glycogen concentration. (GSK, glycogen synthase kinase-3, -4, and -5 G6P, glucose 6-phosphate.)...

Another substrate of PKB is glycogen synthase kinase 3(5 (GSK3(5), whose phosphorylation causes its inactivation. As its name indicates, this protein kinase was originally discovered as a regulator... 

Chen G, Jiang Y et al. The mood stabilising agent valproate inhibits the activity of glycogen synthase kinase 3. J Neurochem 1999 72 1327-1330. 

Sutherland, C., and Cohen, P. (1994). The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 338, 37—42. 

Welsh, G. I., Miller, C. M Loughlin, A. J., Price, N. T., and Proud, C. G. (1998). Regulation of eukaryotic initiation factor eIF2B Glycogen synthase kinase-3 phosphor-ylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS Lett. 421, 125-130. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

Morfini, G., Szebenyi, G., Elluru, R., Ratner, N. and Brady, S. T. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 23 281-293, 2002. 

CDK, cyclin-dependent kinase ERK, extracellular signal-regulated kinase GRK, G protein receptor kinase JNK, Jun kinase MAP kinase, mitogen activated protein kinase MEK, MAP kinase and ERK kinases RSK, ribosomal S6 kinase, GSK, glycogen synthase kinase SAPK, stress-activated protein kinase SEK, SAPK kinase. 

In contrast to inhibitor 1, DARPP-32 and NIPP1, which regulate signal transduction, the function of inhibitor 2 appears to be different. There is evidence that inhibitor 2 associates with PP1, as the phosphatase is newly synthesized and contributes to the proper folding of the enzyme [40]. Inhibitor 2 can thus be considered a chaperone protein. The inactive PP 1-inhibitor 2 complex can then be activated upon phosphorylation of inhibitor 2 by glycogen synthase kinase-3. Whether this process is regulated in neurons in association with synaptic activity remains unknown. 

A crucial kinase that functions as an intermediary in numerous intracellular signaling pathways is the enzyme glycogen synthase kinase-3 (GSK-3) 898... 

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