The conformationally dynamic structural biology of lanthipeptide biosynthesis

Area of Science:

• Biochemistry
• Molecular Biology
• Synthetic Biology

Background:

• Lanthipeptide synthetases are enzymes that create complex cyclic peptides with thioether bridges.
• These peptides often possess valuable therapeutic properties.
• Controlling the macrocyclic topology of lanthipeptides is challenging due to precursor peptide flexibility.

Purpose of the Study:

• To review the diverse strategies used by five classes of lanthipeptide synthetases.
• To explore how these enzymes manipulate peptide conformation for specific outcomes.
• To understand the link between enzyme strategy, topology, and biological activity.

Main Methods:

• Review of existing literature on lanthipeptide synthetases.
• Analysis of phylogenetic divergence among synthetase classes.
• Examination of enzyme-substrate interactions and conformational control mechanisms.

Main Results:

• Five distinct classes of lanthipeptide synthetases employ unique mechanisms.
• Enzyme-guided manipulation of precursor peptide dynamics is crucial for topology.
• Subtle conformational control dictates final product structure and bioactivity.

Conclusions:

• Lanthipeptide synthetases exploit dynamic conformational ensembles of precursor peptides.
• Understanding these enzymatic strategies is key to predicting and engineering lanthipeptide topology.
• This knowledge facilitates the development of novel therapeutic peptides.