The Phormidolide Biosynthetic Gene Cluster: A trans-AT PKS Pathway Encoding a Toxic Macrocyclic Polyketide

Area of Science:

• Marine natural products chemistry
• Molecular biology
• Biochemistry

Background:

• Phormidolide is a 16-membered macrolactone polyketide from a marine cyanobacterium.
• Its complex structure suggests a polyketide synthase (PKS) origin but has unique features.
• The biosynthetic pathway of phormidolide remains largely uncharacterized.

Purpose of the Study:

• To elucidate the biosynthetic origin of phormidolide.
• To characterize the phormidolide gene cluster (phm).
• To reevaluate the stereochemistry of phormidolide based on biosynthetic insights.

Main Methods:

• Stable isotope incorporation experiments to confirm polyketide biosynthesis.
• Genome sequencing and bioinformatic analysis of the phormidolide gene cluster (phm).
• Analysis of acetate incorporation and keto reduction mechanisms.

Main Results:

• Stable isotope experiments confirmed the polyketide nature of phormidolide.
• The phormidolide gene cluster (phm) was identified and characterized.
• Bioinformatic analysis indicated a trans-acyltransferase (trans-AT) PKS pathway.
• Insights into acetate incorporation and keto reduction led to a reevaluation of stereochemistry.

Conclusions:

• Phormidolide biosynthesis involves a trans-AT PKS pathway.
• The study provides a deeper understanding of phormidolide's complex structure and origin.
• Further investigation into the stereochemistry of phormidolide is warranted based on biosynthetic data.