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A High-Yield Streptomyces Transcription-Translation Toolkit for Synthetic Biology and Natural Product Applications
Published on: September 10, 2021
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Development of a Streptomyces-based system for facile thioholgamide library generation and analysis
Maria Lopatniuk1, Florian Riedel1, Julia Wildfeuer2
1Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University, Campus C2.3, 66123, Saarbrücken, Germany.
Metabolic Engineering
|May 4, 2023
Summary
Researchers developed a new method to create diverse thioholgamide natural product derivatives. This facilitates anticancer drug discovery by enabling rapid structure-activity relationship studies and compound optimization.
Area of Science:
- Natural Product Chemistry
- Synthetic Biology
- Medicinal Chemistry
Background:
- Derivatizing natural products (NPs) is crucial for drug development and understanding structure-activity relationships (SAR).
- Ribosomally synthesized and post-translationally modified peptides (RiPPs), like thioholgamide, are a significant class of NPs with therapeutic potential.
- Existing methods for derivatizing RiPPs in Actinobacteria are limited and inefficient.
Purpose of the Study:
- To develop a facile system for producing a library of randomized thioholgamide derivatives.
- To enable comprehensive SAR studies and compound optimization for thioholgamide-based drug development.
- To investigate the impact of amino acid substitutions on thioholgamide post-translational modifications (PTMs).
Main Methods:
- Utilized an optimized Streptomyces host for generating a library of randomized thioholgamide derivatives.
- Employed codon substitutions in the precursor peptide gene to access all possible amino acid substitutions.
- Analyzed 152 potential derivatives, successfully detecting 85 unique compounds.
Main Results:
- Successfully generated a library of randomized thioholgamide derivatives.
- Identified the impact of specific amino acid substitutions on thioholgamide PTMs.
- Discovered novel PTMs, including thiazoline heterocycles and S-methylmethionine, in thioholgamide derivatives.
- Observed thiazoline heterocycles, previously unreported in thioamitides, and rare S-methylmethionine.
Conclusions:
- The developed system provides a rapid and efficient method for thioholgamide derivatization in Actinobacteria.
- The study revealed new insights into thioholgamide PTMs and the influence of amino acid sequence.
- The generated library is valuable for advancing thioholgamide SAR studies and anticancer drug development efforts.
