Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains

Area of Science:

• Biocatalysis
• Organic Chemistry
• Drug Discovery

Background:

• Macrocycles are crucial in drug discovery for selective target binding.
• Developing efficient biocatalysts for macrocyclization remains a significant challenge in chemistry.

Purpose of the Study:

• To explore thioesterase domains (TEs) from natural product biosynthesis as biocatalysts for macrocyclization.
• To investigate the substrate scope and versatility of these TEs in chemoenzymatic synthesis.

Main Methods:

• Utilized TE domains from zearalenone and radicicol biosynthesis.
• Performed chemoenzymatic synthesis of macrolactones and macrolactams.
• Assessed substrate tolerance by testing various acyl chains and depsipeptides.

Main Results:

• TEs successfully synthesized 12- to 18-member macrolactones and a 14-member macrolactam.
• Enzymes demonstrated versatility by macrolactonizing a non-resorcylate depsipeptide.
• Defined substrate limitations, excluding simple saturated and alpha-beta unsaturated acyl chains.

Conclusions:

• TEs are promising and versatile biocatalysts for chemoenzymatic synthesis of diverse macrocyclic structures.
• These enzymes exhibit the broadest substrate tolerance among known polyketide macrocyclizing enzymes.
• Findings expand understanding of TE function and offer new tools for medicinal chemistry.