Structural insights and rational engineering strategies for modular polyketide synthases: A review

Area of Science:

• Biochemistry and Synthetic Biology
• Natural Product Discovery

Background:

• Polyketide synthases (PKSs) are complex enzymatic systems producing diverse natural products like antibiotics.
• Cis-acyltransferase (AT) PKSs are modular, flexible systems with potential in synthetic biology.
• Rational design of cis-AT PKSs is challenging due to interconnected domain functions.

Purpose of the Study:

• To review the multidimensionality of cis-AT PKS design strategies.
• To highlight the importance of structural and mechanistic insights for engineering PKSs.
• To provide a resource for researchers in cis-AT PKS engineering.

Main Methods:

• Focus on selecting modular building blocks for cis-AT PKS.
• Analysis of catalytic domain engineering (acyltransferases, ketosynthases, etc.).
• Review of thioesterase domain engineering for polyketide tailoring.

Main Results:

• Modifications to catalytic domains can fine-tune substrate specificity and stereochemistry.
• Engineering the thioesterase domain allows controlled hydrolysis or cyclization.
• Insights support adapting cis-AT PKS for enhanced product yields and diversity.

Conclusions:

• Cis-AT PKS engineering requires understanding domain interactions for rational design.
• Strategic engineering can expand the repertoire of accessible polyketides.
• This review systematizes cis-AT PKS architecture and engineering approaches.