Ribosomally synthesized and post-translationally modified peptide natural products: new insights into the role of leader and core peptides during biosynthesis

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with a high degree of structural diversity and a wide variety of bioactivities. Understanding the biosynthetic machinery of these RiPPs will benefit the discovery and development of new molecules with potential pharmaceutical applications. In this Concept article, we discuss the features of the biosynthetic pathways to different RiPP classes, and propose mechanisms regarding recognition of the precursor peptide by the post-translational modification enzymes. We propose that the leader peptides function as allosteric regulators that bind the active form of the biosynthetic enzymes in a conformational selection process. We also speculate how enzymes that generate polycyclic products of defined topologies may have been selected for during evolution.

Figure 1

General biosynthetic pathway of RiPPs. RS = recognition sequence.

Figure 2

(A) Biosynthesis of nisin A. (B) Generation of (Me)Lan and labionin motifs.

Figure 3

(A) Three classes of lasso peptides. Residues involved in the macrolactam are shown in red. (B) Structure of microcin J25 as a representative lasso peptide. (C) Righthanded conformation of lasso peptides.

Figure 4

(A) Biosynthesis of microcin B17 as a representative LAP. (B) Generation of oxazol(in)e and thiazol(in)e motifs.

Figure 5

. Proposed biosynthesis of patellamides A and C. The precursor peptide contains an N-terminal leader peptide and two core peptide cassettes. In each cassette, the core peptide sequence is sandwiched between two recognition sequences (purple/green).

Figure 6

Structure of bottromycin A2.

Figure 7

Structure of microviridin B.

Figure 8

Proposed biosynthesis of subtilosin A.

Figure 9

Structures of polytheonamide A and B. The two peptides differ by the configuration of the sulfoxide moiety. Epimerizations are shown in blue, methylation is shown in red, and hydroxylation is shown in purple.

Figure 10

Proposed role of the leader peptide in activating their biosynthetic enzymes. The leader peptide is shown in red. The core peptide is shown in blue. The potential pseudosubstrate domain of the synthetase is shown in purple.

Figure 11

Some representative lanthipeptides. The same shorthand notation is used as in Fig. 2.

Figure 12

Lanthipeptide structures that have been used for studies investigating the role of the core peptide. The same shorthand notation is used as in Figure 2. (Me)Lan residues with unusual stereochemistry are shown in pink.