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Engineered Biosynthesis and Anticancer Studies of Ring-Expanded Antimycin-Type Depsipeptides.
Zhijuan Hu1,2, Di Gu3, Will Skyrud3
1Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States.
ACS Synthetic Biology
|April 29, 2024
Summary
Researchers successfully produced anticancer compounds called respirantins using a synthetic biosynthetic gene cluster. This breakthrough enables easier production and development of novel respirantin-based cancer drugs.
Area of Science:
- Natural Product Chemistry
- Synthetic Biology
- Cancer Pharmacology
Background:
- Respirantins are potent anticancer depsipeptides with complex structures.
- Low natural production titers and synthesis challenges hinder research.
- Previous bioinformatic analysis proposed the respirantin biosynthetic gene cluster.
Purpose of the Study:
- To establish a heterologous system for respirantin production.
- To generate novel respirantin derivatives for drug discovery.
- To elucidate structure-activity relationships for anticancer efficacy.
Main Methods:
- Synthetic biosynthetic gene cluster reconstitution in *Streptomyces albus*.
- Polyketide synthase pathway engineering and biocatalysis.
- Chemical derivatization and cytotoxicity screening (MCF-7, Hela cells).
Main Results:
- Successful heterologous production of respirantins achieved.
- Nine respirantin compounds generated, including six new derivatives.
- Unique biphasic dose-response and essential functional groups identified.
Conclusions:
- The synthetic BGC system provides an accessible platform for respirantin production and diversification.
- Structure-activity relationship studies identified key cytotoxic determinants.
- This work facilitates respirantin-based anticancer drug discovery and development.
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