Macrocyclizing-thioesterases in bacterial non-ribosomal peptide biosynthesis.

Area of Science:

• Biochemistry
• Synthetic Biology
• Medicinal Chemistry

Background:

• Peptide macrocyclization enhances drug properties by reducing flexibility.
• Synthetic challenges include epimerization and oligomerization.
• Non-ribosomal peptide (NRP) biosynthesis offers biocatalytic routes to macrocycles.

Purpose of the Study:

• To review the biocatalytic potential of NRP cyclases for macrocycle synthesis.
• To highlight cis-acting thioesterases as key cyclizing enzymes in NRPs.
• To summarize recent findings on trans-acting thioesterases, including penicillin-binding protein-type enzymes.

Main Methods:

• Literature review of NRP cyclases and thioesterases.
• Analysis of biocatalytic mechanisms for peptide cyclization.
• Summary of established and emerging thioesterase classes.

Main Results:

• NRP cyclases, particularly cis-acting thioesterases, are versatile tools for macrocycle synthesis.
• Penicillin-binding protein-type thioesterases represent a novel class of trans-acting cyclases.
• Biocatalysis simplifies access to complex cyclic peptides.

Conclusions:

• NRP cyclases offer efficient chemoenzymatic strategies for peptide macrocyclization.
• Understanding thioesterase diversity expands biocatalytic toolbox for drug discovery.
• This review provides insights into leveraging biosynthetic machinery for synthetic chemistry.