Borrelidin B: isolation, biological activity, and implications for nitrile biosynthesis
Christopher J Schulze1, Walter M Bray, Frank Loganzo
1Department of Chemistry and Biochemistry, University of California, Santa Cruz , 1156 High Street, Santa Cruz, California 95064, United States.
Journal of Natural Products
|November 14, 2014
Summary
Researchers discovered borrelidin B, a new metabolite related to borrelidin. This finding impacts understanding of nitrile biosynthesis and the bioactivity of borrelidin compounds, showing the nitrile group is essential for tRNA synthetase inhibition but not all biological activity.
Area of Science:
- Biochemistry
- Natural Products Chemistry
- Molecular Biology
Background:
- Borrelidin is a potent inhibitor of bacterial and eukaryotic threonyl-tRNA synthetases.
- Borrelidin is a nitrile-containing polyketide derived from bacteria.
Purpose of the Study:
- To report the discovery of borrelidin B, a novel tetrahydro-borrelidin derivative.
- To investigate the role of the nitrile group in the bioactivity of borrelidin compounds.
- To explore implications for borrelidin biosynthesis.
Main Methods:
- Isolation and structural elucidation of borrelidin B.
- Screening using the SToPS assay for tRNA synthetase inhibition.
- Cytological profiling using an image-based assay.
Main Results:
- Borrelidin B (2) was discovered as a tetrahydro-borrelidin derivative with an aminomethyl group instead of a nitrile.
- The nitrile moiety is essential for threonyl-tRNA synthetase inhibition.
- Borrelidin B retains biological activity, causing a mitotic stall despite lacking the nitrile group.
Conclusions:
- The nitrile group is crucial for borrelidin's tRNA synthetase inhibitory activity.
- Borrelidin B exhibits biological activity independent of the nitrile group, suggesting alternative mechanisms of action.
- The discovery provides insights into borrelidin biosynthesis and the structure-activity relationships within this compound class.
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