Promiscuity of lanthipeptide enzymes: new challenges and applications

Abstract

Lanthipeptides are a group of peptides synthesized by ribosomes that undergo post-translational modifications and have significant potential for medical and biotechnological applications. Various bacterial strains produce these peptides, and their synthesis involves the structural modification of precursor compounds through specialized enzymes present within a biosynthetic gene cluster (BGC) of the producing organisms. These enzymes are particularly notable for their capacity to modify non-cognate substrates, allowing for the installation of lanthionine rings on precursor peptides and enabling further modifications, such as methylation, reduction, and oxidation, to enhance the biological properties of specific peptides. The inherent flexibility of lanthipeptide enzymes-an important characteristic of this class of proteins-can be utilized to create peptides with improved bioactive and physicochemical properties. This review synthesizes recent advances in the application of promiscuous enzymes for the synthesis of bioactive peptides, emphasizing the diverse classes identified to date.

Keywords: Enzymatic promiscuity; Lanthipeptides; Leader peptide; Posttranslational modifications.

Fig. 1

The processing of lanthipeptides: a The biosynthetic pathway of lanthipeptides; b the general mechanisms of lanthionine ring formation across all known lanthipeptide classes today

Fig. 2

Production of hybrid NIS peptides for new peptide variants. a General overview of the production of hybrid peptides. The NIS 1–20/22 segment represents the lipid II-binding site, while a non-cognate peptide is joined at the C-terminal end. b The structure of Ripcin C is depicted as a hybrid peptide combining NIS 1–20 (shown in white) and ripcin (shown in pink), which is a derivative of an antimicrobial peptide (Zhao and Kuipers 2021). c The proposed structure of TL19 is presented as a powerful hybrid lanthipeptide that merges NIS 1–22 (in white) and HalA1 (in green), both of which correspond to lipid II binding sites (Zhao et al. 2020b)

Fig. 3

Structures of peptides produced by promiscuous LanM enzymes. a ProcA 2.8 16RGD and cProcA 2.8 15RGD are derivative peptides of prochlorosin 2.8, featuring the integrin binding epitope RGD (highlighted in brown) (Hegemann et al. ; Le et al. 2024). The latter is a cyclic peptide. b The GLP-1 analog produced by ProcM is resistant to proteolysis by dipeptidyl peptidase IV (DPP-IV) (Larsen et al. 2024). c The H8&H12R lacticin 481 variant contains ornithine at the 8 and 12 positions (illustrated in green) (Xu et al. 2024). d Bioactive cyclic peptides modified by the SyncM enzyme have mutated amino acids in the SyncA precursors, which are highlighted in blue (Arias-Orozco et al. 2023)