Polyketide synthesis: prospects for hybrid antibiotics

Area of Science:

• Biochemistry
• Molecular Biology
• Organic Chemistry

Background:

• Polyketides are natural products synthesized by polyketide synthases (PKSs).
• Two main structural classes of polyketides exist: aromatic and complex.
• Aromatic polyketides are synthesized from acetate units with minimal reduction of beta-carbonyl groups.
• Complex polyketides incorporate various building blocks (acetates, propionates, butyrates) with variable beta-carbonyl reduction.

Purpose of the Study:

• To elucidate the emerging themes in polyketide synthase (PKS) organization and function.
• To differentiate the genetic and enzymatic architectures of aromatic and complex PKSs.
• To explore the potential for generating novel polyketide structures through domain manipulation.

Main Methods:

• Analysis of gene clusters encoding PKS enzymes.
• Characterization of mono- and bifunctional enzymes in aromatic PKSs.
• Investigation of multifunctional polypeptides and enzymatic domains in complex PKSs.
• Introduction of mutations to inactivate specific enzymatic domains in complex PKS genes.

Main Results:

• Aromatic PKSs utilize a single PKS complex encoded by 4-6 genes for all synthesis steps.
• Complex PKSs involve multiple multifunctional polypeptides, each containing distinct enzymatic domains.
• Domain functionality in complex PKSs dictates the extent of beta-carbonyl processing at each cycle.
• Nonfunctional domain mutations in complex PKS genes led to the production of novel polyketide molecules.

Conclusions:

• Distinct PKS architectures correlate with aromatic and complex polyketide biosynthesis.
• The modular nature of complex PKSs offers a framework for combinatorial biosynthesis.
• Targeted domain inactivation presents a viable strategy for discovering new polyketide natural products.