Transformation-Guided Genome Mining Provides Access to Brominated Lanthipeptides.

Area of Science:

• Biocatalysis and Enzyme Engineering
• Natural Product Biosynthesis
• Synthetic Chemistry

Background:

• Natural product biosynthesis offers unique enzymatic transformations beyond traditional chemical catalysis.
• Developing novel enzymes is crucial for expanding synthetic chemistry capabilities.
• Macrocyclic peptides are important scaffolds in drug discovery.

Purpose of the Study:

• To discover and characterize a novel enzyme for modifying macrocyclic peptides.
• To enable biocatalytic access to functionalized macrocyclic peptides.
• To explore new strategies for chemical derivatization of natural products.

Main Methods:

• Genome mining to identify potential enzyme candidates.
• Enzymatic assays to test halogenase activity on peptide substrates.
• Biochemical characterization of the identified halogenase.
• Demonstration of downstream Suzuki-Miyaura coupling.

Main Results:

• Discovery of a halogenase enzyme capable of regioselective bromination.
• The enzyme preferentially acts on macrocyclic peptide substrates over linear ones.
• The resulting aryl-bromide handle facilitates subsequent Suzuki-Miyaura cross-coupling reactions.
• This provides a biocatalytic route to functionalized macrocyclic peptides.

Conclusions:

• A novel halogenase has been identified for the biocatalytic functionalization of macrocyclic peptides.
• This enzyme facilitates the introduction of a versatile aryl-bromide handle onto peptide scaffolds.
• The findings open avenues for the synthesis of diverse macrocyclic peptide derivatives via biocatalysis and chemical coupling.