Manipulating polyketide stereochemistry by exchange of polyketide synthase modules

Area of Science:

• Synthetic biology
• Biochemistry
• Organic chemistry

Background:

• Modular polyketide synthases (PKS) are large enzyme complexes.
• Engineering PKS is essential for altering polyketide structures and functions.
• Controlling polyketide stereochemistry is a significant challenge in PKS engineering.

Purpose of the Study:

• To investigate efficient methods for altering polyketide stereochemistry.
• To compare the efficacy of whole module exchange versus individual domain swapping in PKS engineering.
• To develop novel modular biobricks for synthetic biology applications.

Main Methods:

• Genetic engineering of modular polyketide synthases (PKS).
• Comparative analysis of whole module versus ketoreductase (KR) domain exchange.
• Characterization of stereochemical outcomes in model polyketides.

Main Results:

• Exchanging whole PKS modules proved more productive than swapping individual ketoreductase (KR) domains.
• This approach successfully introduced rare 'A2' and 'B2' stereochemistry into model polyketides.
• Four novel modular biobricks were identified for synthetic biology.

Conclusions:

• Whole module exchange is a superior strategy for stereochemical control in PKS engineering.
• The identified biobricks facilitate the construction of novel polyketide architectures.
• This work advances the field of synthetic biology for natural product synthesis.