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Studies on the biosynthesis of avermectins
1Department of Fermentation Microbiology, Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Archives of Biochemistry and Biophysics
|May 1, 1989
Summary
Researchers studied avermectin biosynthesis using 14C-labeled compounds in Streptomyces avermitilis. Two novel furan ring-free aglycones were identified as key intermediates preceding avermectin aglycones in the pathway.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Avermectins are complex macrocyclic lactones with significant biological activity.
- Understanding the avermectin biosynthetic pathway is crucial for metabolic engineering and drug discovery.
- Previous studies have identified key enzymes and precursors, but the precise sequence of aglycone formation remained unclear.
Purpose of the Study:
- To elucidate the biosynthetic pathway of avermectins.
- To identify novel intermediates in avermectin biosynthesis.
- To establish the relationship between specific aglycones and the final avermectin products.
Main Methods:
- Utilized 14C-labeled acetate to trace metabolic flux in Streptomyces avermitilis.
- Isolated and characterized novel furan ring-free aglycones from blocked mutant fermentation broths.
- Performed feeding experiments with isolated intermediates and a semisynthetic compound in a second blocked mutant.
Main Results:
- Two furan ring-free aglycones, 6,8a-seco-6,8a-deoxy-5-keto avermectin B1a and B2a, were isolated.
- These compounds were confirmed as intermediates immediately preceding avermectin aglycones in the biosynthetic pathway.
- Feeding experiments validated the role of these aglycones in avermectin formation.
Conclusions:
- The identified furan ring-free aglycones represent critical intermediates in avermectin aglycone biosynthesis.
- This study refines our understanding of the avermectin metabolic pathway.
- The findings provide targets for future genetic manipulation to enhance avermectin production.