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Related Experiment Videos

Polyketide synthase gene manipulation: a structure-function approach in engineering novel antibiotics

C R Hutchinson1, I Fujii

  • 1School of Pharmacy, University of Wisconsin, Madison 53706, USA.

Annual Review of Microbiology
|January 1, 1995
PubMed
Summary

Polyketides, microbial compounds derived from fatty acid synthesis, are produced by two main enzyme systems. Gene expression studies reveal their biochemistry and can yield novel natural products.

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Area of Science:

  • Biochemistry
  • Microbiology
  • Molecular Biology

Background:

  • Polyketides are microbial secondary metabolites closely related to fatty acid biosynthesis.
  • Enzymes involved in polyketide synthesis share similarities with fatty acid synthases, leading to distinct biochemical models.
  • Understanding polyketide biosynthesis is crucial for discovering novel natural products.

Purpose of the Study:

  • To elucidate the two primary paradigms of polyketide biosynthesis.
  • To explore the biochemical mechanisms underlying polyketide synthase (PKS) function.
  • To investigate the potential for generating novel compounds through PKS gene manipulation.

Main Methods:

  • Comparative analysis of fatty acid synthase (FAS) and polyketide synthase (PKS) enzymes.

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  • Biochemical characterization of two distinct PKS models: one with monofunctional enzymes and another with multifunctional enzymes.
  • Gene expression studies of PKS genes and their mutant forms.

    • Main Results:

    • Two models for polyketide biosynthesis were identified: one yielding aromatic compounds from unreduced intermediates and another producing highly reduced compounds from various acyl-CoA residues.
    • The monofunctional enzyme model involves 4-7 proteins where intermediates are minimally reduced.
    • The multifunctional enzyme model processes intermediates through multiple reduction, dehydration, and reduction cycles.

    Conclusions:

    • The study clarifies the biochemical diversity in polyketide synthesis pathways.
    • Expression of PKS genes, including mutant variants, offers insights into polyketide biochemistry.
    • This research opens avenues for the discovery of new natural products through synthetic biology approaches.