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From a Natural Product to Its Biosynthetic Gene Cluster: A Demonstration Using Polyketomycin from Streptomyces diastatochromogenes Tü6028
Published on: January 13, 2017
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Macrodiolide formation by the thioesterase of a modular polyketide synthase
Yongjun Zhou1, Patrícia Prediger, Luiz Carlos Dias
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA (UK).
Angewandte Chemie (International Ed. in English)
|March 11, 2015
Summary
Researchers reconstituted macrodiolide formation in vitro using a synthetic precursor. This revealed the elaiophylin thioesterase
Area of Science:
- Biochemistry
- Synthetic Biology
- Natural Product Synthesis
Background:
- Elaiophylin is a C2-symmetric antibiotic macrodiolide synthesized by bacterial modular polyketide synthases.
- Understanding the mechanism and selectivity of diolide ring formation is crucial for biosynthesis and drug development.
Purpose of the Study:
- To investigate the in vitro mechanism of elaiophylin macrodiolide formation.
- To explore the potential of elaiophylin thioesterase as a tool for novel diolide synthesis.
Main Methods:
- Reconstitution of ring formation using a synthetic pentaketide N-acetylcysteamine thioester analogue.
- Incubation of recombinant elaiophylin thioesterase/cyclase with synthetic polyketide precursors.
Main Results:
- A novel 16-membered C2-symmetric macrodiolide was produced from a synthetic pentaketide precursor.
- A linear dimeric thioester intermediate was identified, indicating iterative active site use.
- Elaiophylin thioesterase produced both symmetric decaketide and asymmetric nonaketide diolides when acting on mixed precursor thioesters.
Conclusions:
- The elaiophylin thioesterase/cyclase can catalyze the formation of novel macrodiolides from non-natural substrates.
- Iterative ligation and cyclization mechanisms are involved in diolide ring formation.
- Elaiophylin thioesterases show promise as versatile tools for in vitro synthesis of diverse diolides.
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