Ribosomally synthesized and post-translationally modified peptide natural product discovery in the genomic era

Abstract

In the past 15 years, the cost of sequencing a genome has plummeted. Consequently, the number of sequenced bacterial genomes has exponentially increased, and methods for natural product discovery have evolved rapidly to take advantage of the wealth of genomic data. This review highlights applications of genome mining software to compare and organize large-scale data sets and methods for identifying unique biosynthetic pathways amongst the thousands of ribosomally synthesized and post-translationally modified peptide (RiPP) gene clusters. We also discuss a small number of the many RiPPs discovered in the years 2014-2016.

Figure 1

General biosynthetic pathway for RiPPs. Note that the precursor peptides can contain a leader peptide, a follower peptide, or both.

Figure 2

RiPP-PRISM genome mining results of 65,421 prokaryotic genomes. The area of the rectangles in the bottom half of the picture correspond to the relative number of clusters found. Figure generated using data from [19].

Figure 3

Structures of RiPPs characterized from a bottom-up discovery approach. Note that the tail of citrulassin is threaded through the ring similar to caulonodin V; however, to show the citrulline side chain it is shown unthreaded. Post-translational modifications are colored as follows. Red: bonds formed during cyclization, blue: dehydration, purple: thiazol(in)es/oxazol(in)es, orange: citrulline, green: novel Ser/Leu residue at position 1 in caulonodin V and citrulassin. Dhb: dehydrobutyrine, Abu: α-aminobutyric acid, Cit: citrulline.

Figure 4

Structures of RiPPs discovered via a genomics-aided top-down approach. Posttranslational modifications are colored as follows. Red: bonds formed during cyclization, blue: dehydrogenation (phomopsin A) or dehydration, green: epimerization, cerulean: hydroxylation, purple: thiazol(in)es/oxazol(in)es, orange: methylation, yellow oval: other post-translational modification. Dhb: dehydrobutyrine, Abu: α-aminobutyric acid.