Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti‐Cancer Properties

Abstract

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF-1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti-cancer compound didemnin B on EF-1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1.

Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes

“…Based on this observation, we propose a conserved mechanism (Schmeing et al., 2009) that didemnin B serves to increase the effective number of contacts between the GDP-bound G domain and domain 3 to prevent the inter-domain rotation that is necessary for eEF1A to release aa-tRNA and dissociate from the ribosome. Recently, didemnin B and ansatrienin B have been shown to compete with ternatin for binding to eEF1A (Carelli et al., 2015), and mutations in eEF1A Ala399, adjacent to the β15-β16 hairpin, were found to confer decreased sensitivity to didemnin B, ternatin, and another structurally unrelated natural product, nannocystin A (Carelli et al., 2015, Krastel et al., 2015). This suggests that these chemically diverse natural products share similar mechanisms of activity.…”

Natural products as probes in pharmaceutical research

“…A refined version of this experiment adds a dose-dependent competition step of the bound proteins using defined concentrations of unbound compound resulting in fewer false-positive hits. This report presents examples of successful application of this technology (OSW1: [6], cyclomarin A: [5,54], nannocystin A: [30]). The requirement to immobilize the lead compound using a suitable chemical linker can comprise a resource-intensive task especially in the context of natural compounds that might not be available in large amounts or amenable for simple chemical derivatization.…”

“…2) [25,30], was determined to be the eukaryotic translation elongation factor 1α (EF-1α). The target for this compound was confirmed by the application of different technologies including HIP in yeast, chemical proteomics, profiling in the cell line panel and sequencing of a resistance cancer cell line [30].…”

“…2) [25,30], was determined to be the eukaryotic translation elongation factor 1α (EF-1α). The target for this compound was confirmed by the application of different technologies including HIP in yeast, chemical proteomics, profiling in the cell line panel and sequencing of a resistance cancer cell line [30]. Nannocystin A not only shares the same target but also a conserved binding site with didemnin B, a marine natural product that shows promising results in pre-clinical settings for the treatment of cancers [55].…”

Molecular and functional characterization of myxobacteria isolated from soil in India

“…Recently, nannocystin from Nannocystis sp. has been found to show activity against various cancer cell lines by targeting eukaryotic translation (Krastel et al 2015).…”