The lanthipeptide biosynthetic clusters of the domain Archaea.

Research on Archaea's secondary metabolites is still lagging behind that of Bacteria and Eukarya. Our goal was to contribute to this knowledge gap by analyzing the lanthipeptide's clusters in Archaea. As previously proposed, Archaea encodes only class II synthetases (LanMs), which we found to be confined to the class Halobacteria (also known as haloarchaea). In total, we analyzed the phylogeny and the domains of 42 LanMs. Four types were identified, and the majority of them belong to the CCG group due to their cyclization domain, which includes LanMs of Cyanobacteria. Putative cognate peptides were predicted for most of LanMs and are a very diverse group of molecules that share a Kx(Y/F)(D/E)xx(F/Y) motif in their leader peptides. According to their homology, some of them were categorized into subfamilies, including Halolancins, Haladacins, Haloferaxcins and Halobiforcins. Many LanM genes were associated with mobile genetic elements, and their vicinities mainly encode ABC and MFS transporters, tailoring enzymes and uncharacterized proteins. Our results suggest that the biosynthesis of lanthipeptides in haloarchaea can entail distinct enzymology that must lead to the production of peptides with novel structures and unpredicted biological and ecological roles. Finally, an Haloferax mediterranei knockout, lacking its three lanM genes, was generated, and it was concluded that its antimicrobial activity is not primarily related to the production of lanthipeptides.