Mechanistic Aspects of Lanthipeptide Leaders
Gert N. Moll.
Lanthipeptides are ribosomally synthesized and posttranslationally modified peptides produced by microorganisms.
The name lanthipeptide is derived from lanthionine, a thioether–bridged amino acid installed by dedicated modification
enzymes. Serines and threonines are dehydrated and subsequently coupled to cysteines, thus forming intramolecular
lanthionine rings. A well–known subclass of lanthipeptides are lantibiotics: lanthipeptides with antimicrobial activity. The
lantibiotic nisin is applied worldwide in the food industry to prevent food spoilage. This review focuses on lanthipeptide
leader peptides, which have a crucial and central role in lanthipeptide biosynthesis. Lanthipeptide leader peptides are present
at the N–terminus within precursor lanthipeptides. Intriguingly, a single leader peptide can interact with highly different
modifying enzyme(s) (domains) and furthermore induce export out of the cell via a dedicated export protein. Eventually
the leader peptide is cleaved off by a leader peptidase, either extracellularly or intracellularly as part of the transporter.
Recent exciting mechanistic and engineering studies ignited the unraveling of the fascinating interactions of lanthipeptide
leader peptides with the lanthipeptide modification enzymes and transporters. The biosynthesis of at least some
lanthipeptides is performed by a highly flexible enzyme system. Novel lantibiotics can be synthesized by fusing lanthipeptide
leader peptides to completely different silent lantibiotics obtained by genome mining. Moreover, the fusion of leader
peptides to the N–terminus of medically and economically important therapeutic peptides has resulted in lanthioninestabilized
therapeutics with enhanced bioavailability and optimized receptor interaction.
Keywords: Lanthipeptide, lanthionine, lantibiotic, leader, nisin, dehydratase, cyclase
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