Anti-inflammatory Potential of GSK-3 Inhibitors

Glycogen synthase kinase-3 (GSK-3) is a protein kinase containing threonine or serine amino acid residues. GSK-3 was first discovered in 1980 as a regulatory protein kinase, Glycogen synthase (GS) enzyme, which is responsible for the conversion of glycogen from glucose with the help of uridine diphosphate glucose (UDP-Glu) residue. GSK-3 has two isoforms present in human beings, namely GSK-3 alpha (serine residue at 21 position) and GSK-3 beta (serine residue at 9 position). GSK-3 has two terminals, namely C-terminal and N-terminal. C-terminal of GSK-3 resembles alpha-helix conformation, which acts as an activator loop and is responsible for positioning residues in ATP binding and catalysis of substrates. On the other hand, the N-terminal of GSK-3 resembles beta-strand conformation, which acts as an inhibitory loop; having a tyrosine molecule at 216 positions, it is essential for the complete GSK-3 activity. N-terminal of GSK-3 is responsible for ATP bind-ing activity and exhibits various biological activities like cell signaling, gene induction following activation of T cell receptor, apoptosis, protein translation, glycogen metabolism, and inflammato-ry process. Activation of GSK-3 leads to pro-inflammatory actions, i.e. an increase in the binding activity of NF-kB (pro-inflammatory genes), increase in the transactivation activity of NF-kB, in-crease in the phosphorylation of p105, and a decrease in the transactivation activity of C/EBP beta (an-ti-inflammatory genes), resulting in a large number of prevalent diseases such as diabetes, cancer, neurodegenerative diseases, psychiatric diseases, mood disorders, etc. Glycogen synthase kinase inhibitors (GSK-3 inhibitors) are various chemotypes and have different mechanisms of actions. They are obtained from different sources such as natural products, synthet-ic ATP as well as non-ATP competitive inhibitors along with substrate-competitive inhibitors. The inhibitors of GSK3 have proven to possess very potent anti-inflammatory action. GSK-3 inhibitors are useful for treating different prevalent disorders, such as neurodegenerative diseases, including Alzheimer's disease, hyperglycemia, cancer disease, and mood disorders like depression,etc. In this review, we have highlighted the evidence regarding the description and types of GSK, inflam-mation process, and the factors affecting inflammation, the relationship between inflammation and GSK, GSK3 inhibitors, and finally, the impact of various natural as well as synthetic GSK3 inhibi-tors having anti-inflammatory activity.

Automated summary

GSK-3 is a crucial protein kinase with two isoforms, GSK-3α and GSK-3β. It plays important roles in cell signaling, gene induction, apoptosis, protein translation, glycogen metabolism, and inflammatory processes.