Title:Anti-inflammatory Potential of GSK-3 Inhibitors
Volume: 22
Issue: 13
关键词:
GSK-3
摘要:
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 α (serine residue at 21 position) and GSK-3 β (serine residue at 9 position).
GSK-3 has two terminals, namely C- terminal and N- terminal. C-terminal of GSK-3 resembles α-
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 β-
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 binding
activity and exhibits various biological activities like cell signaling, gene induction following
activation of T cell receptor, apoptosis, protein translation, glycogen metabolism, and inflammatory
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, increase
in the phosphorylation of p105, and a decrease in the transactivation activity of C/EBPβ (anti-
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, synthetic
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, inflammation
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 inhibitors
having anti-inflammatory activity.
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