A. James Link, Professor, Chemistry & Biological Engineering, Princeton University, will give a talk on "Lasso Peptide Genome Mining for New Enzyme Discovery"

ABSTRACT

Lasso peptides are a class of ribosomally synthesized and posttranslationally modified peptides (RiPPs) that are typified by a chiral rotaxane structure that resembles a slipknot.  Lasso peptides exhibit a range of bioactivities including targeted antimicrobial activities.  Our group pioneered genome mining for lasso peptides in 2012, showing that gene clusters for these peptides are present in 2-3% of all sequenced prokaryotic genomes.  This percentage has held true as the number of sequenced genomes has grown from ~3000 in 2011 to well over 200000 today.  Because of the diversity in size and sequence inherent in lasso peptides, the rediscovery rate of these natural products is low.  In addition to uncovering lasso peptides with novel structures, properties, and activities, searching genomes for lasso peptide gene clusters has led to the discovery of new enzymes, two of which I will describe in this talk.  The first, lasso peptide isopeptidase, is a lasso peptide catabolic enzyme that converts the slipknotted lasso structure into a linear peptide.  This enzyme suggests a novel function for lasso peptides and also provides a glimpse into how enzymes cope with substrates that are subject to genetic drift.  More recently, we have characterized a new toxin-antitoxin pair that was embedded within a lasso peptide gene cluster.  The toxin is a new example of an ADP-ribosyltransferase, and it modifies an essential enzyme for nucleotide biosynthesis.  Structural analysis of the toxin suggests a novel, potentially ancient, catalytic solution to the problem of ADP-ribosylation.