Hybrid Type I and II Polyketide Synthases Yield Distinct Aromatic Polyketides

Area of Science:

• Microbiology
• Biochemistry
• Synthetic Biology

Background:

• Bacterial aromatic polyketides are synthesized by type II polyketide synthases (PKSs), with some developed into clinical drugs.
• Hybrid polyketides synthesized by both type I and type II PKSs are exceptionally rare in nature.

Purpose of the Study:

• To report the discovery and characterization of a novel hybrid polyketide, spirocycline A.
• To elucidate the unique biosynthetic pathway involving both type I and type II PKSs.

Main Methods:

• Extensive bioinformatics analysis to identify a unique gene cluster.
• Characterization of the hybrid polyketide spirocycline A.
• Biosynthetic studies using identified enzymes and gene clusters.

Main Results:

• Discovery of a gene cluster encoding modular type I PKS, type II PKS, and KAS III.
• Characterization of spirocycline A, a hybrid aromatic polyketide with a unique starter unit and four spirocycles, forming a dimer.
• Elucidation of a novel biosynthetic pathway involving collaborative action of type I PKS, KAS III, and redox enzymes.

Conclusions:

• Spirocycline A represents a rare class of hybrid aromatic polyketides.
• The identified gene cluster and biosynthetic pathway offer new strategies for discovering and engineering novel polyketides.
• The enzymes involved present potential tools for bioengineering hybrid polyketides.