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Biosynthesis of the Apoptolidins in Nocardiopsis sp. FU 40

Yu Du1, Dagmara K Derewacz, Sean M Deguire

  • 1Departments of Chemistry and Biochemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842-3012, U.S.A.

Tetrahedron
|August 27, 2011
PubMed

Insights

Apoptolidins, potent apoptosis inducers, are synthesized by Nocardiopsis sp. FU40. Researchers identified and validated the apoptolidin biosynthetic gene cluster, revealing novel initiation mechanisms for polyketide synthase.

Area of Science:

  • Natural Product Biosynthesis
  • Molecular Biology
  • Microbial Genetics

Background:

  • Apoptolidins are macrolides produced by Nocardiopsis sp. FU40.
  • These compounds selectively induce apoptosis in cancer cell lines, likely through mitochondrial targets.

Purpose of the Study:

  • To investigate the biosynthesis of apoptolidins.
  • To identify and characterize the apoptolidin biosynthetic gene cluster.

Main Methods:

  • Genome sequencing of Nocardiopsis sp. FU40.
  • Identification and cloning of a 116 Kb gene cluster.
  • Functional validation via gene disruption and complementation studies.

Main Results:

  • A type I polyketide synthase gene cluster with 13 modules was identified.
  • An unprecedented initiation mechanism involving a methoxymalonyl-acyl carrier protein loading module was discovered.
  • Gene disruption studies confirmed the roles of PKS and P450 genes in biosynthesis.

Conclusions:

  • Detailed insights into apoptolidin biosynthesis were obtained.
  • The identified gene cluster provides a foundation for generating novel apoptolidin analogs through mutasynthesis.

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