Introduction
Anisomycin, also known by its trade name flagecidin, is a bacterial pyrrolidine antibiotic mostly isolated from Streptomyces griseolus, but it can also be produced from various Streptomyces species. It is primarily an antiprotozoal agent with little antibacterial or antifungal activity. Anisomycin is known mainly as a potent and reversible inhibitor of protein synthesis in eukaryotic organisms but is inactive against bacteria. It also produces a ribotoxic effect that causes activation of stress-activated protein kinases (SAPKs), and also gene superinduction. The chemical name for anisomycin is 2-pmethoxyphenylmethyl-3-acetoxy-4-hydroxypyrrolidine, and its chemical structure is shown in Fig. 1. Anisomycin requires its pyrrolidine ring for its translational inhibitory activity; any change such as an acetylation of the nitrogen or a deacetylation at the 3’ position renders the molecule inactive. The acetyl group at the 3’ position of pyrrolidine ring is crucial for signaling, since deacetyl-anisomycin loses the ability to activate SAPKs and induce immediate-early genes.
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Fig. 1 Anisomycin general structure ( Marina et al , 2010 )
Function
Protein Synthesis Inhibition
Anisomycin is one of the most potent protein synthesis inhibitors (PSIs). It inhibits translation by binding to 60S ribosomal subunit from the 80S ribosome system of eukaryotic cells; thereby it blocks the peptide bond formation, prevents elongation and causes polyribosome stabilization by suppressing the peptidyl transferase reaction. Anisomycin inhibits protein synthesis in some protozoa, HeLa cells, rabbit reticulocytes, yeast, and cell-free extracts prepared from these sources, but it is inactive against extracts from E. coli.
Ribotoxic Stress and MAPK Activation
Ribotoxic stress response is a cellular reaction to ribotoxins, which are cytotoxic proteins characterized by their site-directed action on eukaryotic ribosomes that lead to inhibition of protein synthesis. Ribotoxins interact with the 3’-end of the large 28S rRNA, altering the peptidyl transferase activity of actively translating eukaryotic ribosomes. During protein synthesis, this region of the ribosome functions in aminoacyl-tRNA binding, peptidyl transferase activity, and ribosomal translocation. Thus, the ribotoxic stress response mainly originates from the blockage of the ribosome cycle.
Regulation of Gene Expression
Regulation of gene expression is another intriguing effect of anisomycin, in view of the fact that it is able to superinduce the expression of certain genes, or to cause the degradation of some proteins. Gene superinduction is a phenomenon characterized by augmented and prolonged expression of immediate-early genes that are usually induced transiently, and it is conventionally regarded as a secondary consequence of translational arrest. Several mechanisms may contribute to gene superinduction such as: increased mRNA stability, augmented gene transcription, decreased synthesis of gene repressors, and stimulation of nuclear signaling responses.
Protein Degradation Modulation
Anisomycin is also able to cause the degradation of certain proteins via ubiquitin-proteasome system (UPS), and through mechanisms dependent on and independent of MAPKs activation. For instance, activation of p38 by anisomycin leads to reduction in the levels of phosphorylated Cx43 (connexin 43) possibly via degradation, which might be responsible for the reduction in number of gap junctions and levels of GJIC (gap junctional intracellular communication) protein in liver epithelial cells.
Potential Clinical Applications
Anisomycin was originally identified as an antibiotic against certain protozoa and fungi, which led to proposed clinical uses as an anticandidal and antiamoebic drug in humans. Later, due to its ability to arrest translation it has been commonly used in studying neuronal processes related to memory and learning in animals, although more studies need to be done in order for anisomycin to be considered as a potential psychiatric drug in humans. Nevertheless, anisomycin may have potential clinical significance since it exhibits many biological and pharmacological properties including antitumoral, antiviral, cancer cell death sensitizer and immunosuppressive activities:1) Anisomycin Sensitizes Resistant Cells to Death; 2) Anisomycin´s Immune System Effects; 3) Anisomycin´s Neuronal Effects.
Reference:
Marina, M. S., Genaro V. V. and Jacqueline H. D. (2010). 'Anisomycin is a Multifunctional Drug: More than Just a Tool to Inhibit Protein Synthesis’, Current Chemical Biology, 4(2), 124-132.
