Biochemical Studies of Nisin Biosynthesis and Autoimmunity

Lantibiotics derive their name from the unusual amino acid lanthionine, which consists of two alanine residues cross‐linked by a thioether bridge that connects their β‐carbons. Although the presence of the lanthionine thioether bridge is the characteristic structural motif found in all lantibiotics, they may also contain dehydrated amino acids such as 2,3‐didehydroalanine (Dha) and 2,3‐didehydrobutyrine (Dhb) as well as a methyl‐substituted lanthionine derivative (2 S ,3 S ,6 R )‐3‐methyllanthionine. Lantibiotics possess high levels of antimicrobial activity against several pathogenic gram‐positive bacteria such as staphylococci, streptococci, and clostridia, and nisin, the prototypical lantibiotic, has been used extensively as a commercial food preservative. Despite the widespread use of nisin as a food preservative and its presence since antiquity, nisin still possesses unfettered cytotoxicity against Gram‐positive bacteria with no significant environmental resistance being demonstrated. The lantibiotic nisin is a 34‐residue bacteriocin produced by the Gram‐positive bacteria Lactococcus lactis spp where it is first ribosomally synthesized as an inactive precursor and then post‐translationally modified into its mature biologically active form. Described herein is a two‐part study investigating (1) the basis of how the characteristic nisin lanthionine rings are installed by the enzyme NisC and (2) how Lactococcus lactis spp. is able to demonstrate an autoimmunity to the toxic effects of nisin despite producing such an effective bacteriocin such as nisin. Funding: American Cancer Society, NIH NIDA Individual NRSA (1F30DA019363), and the University of Illinois Institute for Genomic Biology.