Complex peptide natural products: Biosynthetic principles, challenges and opportunities for pathway engineering

Area of Science:

• Biochemistry
• Molecular Biology
• Synthetic Biology

Background:

• Complex peptides possess diverse biological functions and physicochemical properties, leading to clinical applications.
• Nature utilizes two primary peptide biosynthesis strategies: ribosomally synthesized and post-translationally modified peptides (RiPPs) and non-ribosomal peptide synthetases (NRPSs).

Purpose of the Study:

• To contrast the key principles of RiPP and NRPS biosynthetic routes.
• To compare biochemical strategies for peptide modifications.
• To illustrate the influence of biosynthetic principles on peptide engineering.

Main Methods:

• Comparative analysis of RiPP and NRPS biosynthetic pathways.
• Review of biochemical strategies for peptide modification.
• Examination of engineering approaches for peptide production.

Main Results:

• Universal principles governing RiPP and NRPS biosynthesis have been identified.
• Significant overlap exists in peptide modifications utilized by both RiPP and NRPS systems.
• Biocatalytic toolboxes for peptide modification are continuously expanding.

Conclusions:

• Knowledge of RiPP and NRPS pathways facilitates the identification of novel peptide biosynthetic blueprints.
• Engineering efforts can leverage universal principles for rational pathway design.
• Expanding biocatalytic toolboxes enable the production of tailor-made peptides and cross-route production (e.g., NRPS peptides via ribosomal routes).