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Engineering broader specificity into an antibiotic-producing polyketide synthase

A F Marsden1, B Wilkinson, J Cortés

  • 1Cambridge Centre for Molecular Recognition and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.

Science (New York, N.Y.)
|January 31, 1998
PubMed
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Researchers engineered a novel hybrid enzyme by combining parts of avermectin and erythromycin polyketide synthases. This allows for the creation of new antibiotic macrolide analogs using diverse starter units.

Area of Science:

  • Biochemistry
  • Synthetic Biology
  • Microbial Biotechnology

Background:

  • Polyketide synthases (PKS) are large multienzyme complexes responsible for producing a vast array of natural products, including antibiotics.
  • Avermectin and erythromycin are important macrolide antibiotics produced by distinct PKS systems with different substrate specificities.
  • Modifying PKS loading modules offers a strategy to alter the starter units incorporated into the polyketide chain, leading to novel analogs.

Purpose of the Study:

  • To investigate the feasibility of creating novel antibiotic macrolides by swapping the loading module of one PKS with that of another.
  • To engineer a hybrid polyketide synthase by combining the avermectin loading module with the erythromycin PKS scaffold.
  • To characterize the products generated by the engineered hybrid enzyme in a heterologous host.

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Main Methods:

  • Genetic engineering to replace the loading module of the erythromycin-producing polyketide synthase (DEBS1) with the wide-specificity loading module from the avermectin PKS.
  • Heterologous expression of the engineered hybrid enzyme in Saccharopolyspora erythraea.
  • Analysis of the resulting macrolide products using analytical techniques to determine their structures.

Main Results:

  • The hybrid enzyme successfully produced novel erythromycin analogs in Saccharopolyspora erythraea.
  • These novel erythromycins incorporated endogenous branched-chain acid starter units, characteristic of avermectin natural products.
  • The avermectin loading module demonstrated its ability to accept and utilize alternative starter units within the erythromycin PKS framework.

Conclusions:

  • Swapping PKS loading modules is an effective strategy for generating novel macrolide antibiotic analogs.
  • This approach facilitates the production of diverse macrolide structures by leveraging the broad substrate specificity of the avermectin loading module.
  • The engineered hybrid enzyme system provides a powerful platform for the discovery and development of new antibiotic macrolides.