Maturation and secretion of nisin A from Lactococcus lactis

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Nisin A (NisA) is the best-known lantibiotic, a peptide antibiotic that is characterized by the presence of thioether rings called (methyl)lantionine depending on the non-natural amino acids that forms the ring. In the case of NisA five rings are present. NisA is ribosomally synthesized as a precursor containing a leader sequence of 23 amino acids and active NisA, composed of 34 amino acids that possess antimicrobial activity against Gram-positive bacteria. The operon responsible for NisA synthesis consists of 11 genes, four of which are involved in the maturation and secretion. The maturation steps involve dehydration of serine and threonine residues to form dehydroalanine (Ser) and dehydrobutyrine (Thr), respectively. This step is catalyzed by the dehydratase NisB. Subsequently, the cyclase NisC catalyzes the cyclization step resulting in fully modified NisA and ring formation. Finally, fully modified NisA is secreted by the ABC transporter NisT and converted into its biological active form (NisA) by the action of the serine protease NisP, which removes the leader sequence in the extracellular medium. Here, we like to gather biochemical, biophysical and structural knowledge to understand the complex interplay of four enzymes that result in the formation of a biological active lantibiotic.