Modular Halogenation, α-Hydroxylation, and Acylation by a Remarkably Versatile Polyketide Synthase.

Area of Science:

• Biochemistry
• Molecular Biology
• Natural Product Synthesis

Background:

• Bacterial multimodular polyketide synthases (PKSs) are crucial for synthesizing bioactive natural products.
• PKS catalysis shares principles with fatty acid biosynthesis but allows for further diversification by post-PKS enzymes.

Purpose of the Study:

• To characterize a versatile trans-acyltransferase (trans-AT) PKS from Serratia.
• To identify novel enzymatic modules within the oocydin PKS for understanding complex macrolide biosynthesis.

Main Methods:

• Enzymatic characterization of the oocydin PKS.
• Identification and functional analysis of novel PKS modules.

Main Results:

• Characterized a trans-AT PKS with over ten distinct modules responsible for complex macrolide synthesis.
• Identified a novel oxygenation module for α-hydroxylation of polyketide intermediates.
• Discovered a halogenating module for backbone γ-chlorination and modular O-acetylation by a thioesterase-like domain.

Conclusions:

• The oocydin PKS showcases the extensive biochemical capabilities of trans-AT PKSs.
• The identified modular enzymatic tools can be utilized for engineered biosynthesis.