A Peptidyl-Transesterifying Type I Thioesterase in Salinamide Biosynthesis.
Lauren Ray1, Kazuya Yamanaka1,2, Bradley S Moore3,4
1Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92037 (USA) http://scrippsscholars.ucsd.edu/bsmoore.
Angewandte Chemie (International Ed. in English)
|November 11, 2015
Summary
Researchers uncovered the biosynthetic pathway for salinamide A, a complex bicyclic depsipeptide antibiotic. A novel thioesterase enzyme in Streptomyces sp. CNB-091 catalyzes a key transesterification reaction, forming the unique acylglycine "basket handle".
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
- Natural Product Synthesis
Background:
- Salinamide A is a rare bicyclic depsipeptide antibiotic.
- Its structure features a complex hexadepsipeptide core and a unique (4-methylhexa-2,4-dienoyl)glycine "basket handle".
- The biosynthetic pathway for salinamide A was previously unknown.
Purpose of the Study:
- To elucidate the genetic and biochemical basis of salinamide A biosynthesis in Streptomyces sp. CNB-091.
- To identify the key enzymes and reactions involved in constructing the unique acylglycine handle.
Main Methods:
- Genetic analysis of Streptomyces sp. CNB-091.
- Heterologous expression of the nonribosomal peptide synthetase Sln9.
- Biochemical characterization of the Sln9 thioesterase domain.
Main Results:
- Identified a novel intermolecular transesterification reaction catalyzed by a type I thioesterase.
- Demonstrated the crucial role of the nonribosomal peptide synthetase Sln9 in forming the acylglycine "basket handle".
- Biochemical assays confirmed that the Sln9 thioesterase domain mediates the transesterification of desmethylsalinamide E with acylated glycyl thioesters to produce desmethylsalinamide C.
Conclusions:
- The study reveals the complete biosynthetic pathway for salinamide A.
- A novel thioesterase-catalyzed transesterification is essential for constructing the characteristic acylglycine moiety.
- These findings provide insights into the biosynthesis of complex depsipeptide natural products.
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