3/27/2023 0 Comments Dna enzymex online server![]() ![]() The genome sequencing efforts of the past decade have revealed that many classes of peptide natural products that were initially believed to be made by nonribosomal peptide synthetases are in fact made via a ribosomally synthesized precursor peptide that is then heavily post-translationally modified. Lanthipeptides are members of the rapidly expanding RiPP family of natural products. Thioether cross-links are also found in other peptide natural products, but their biosynthesis does not involve this specific sequence of events and they have therefore not been included in the lanthipeptide family. The lanthipeptide family encompasses any peptide containing a (methyl)lanthionine or a (methyl)labionin provided it is made by dehydration of Ser/Thr and subsequent attack by a Cys residue onto a dehydro amino acid. (9) At present, no labionin-like structures have been reported in which the electrophile in the second conjugate addition was a Dhb. Upon protonation, the structure that now introduces two cross-links and contains an α,α-disubstituted amino acid at its center is called a labionin (Lab) when formed from one Cys and two Ser residues, (10) or methyllabionin (MeLab) when formed from one Cys, a central Thr, and an N-terminal Ser ( Figures 1 and 2). Alternatively, the initially formed enolate can attack another dehydro amino acid to produce a carbon–carbon cross-link and a second enolate. The resultant enolate can be protonated to produce either a lanthionine (Lan) from Ser or a methyllanthionine (MeLan) from Thr ( Figure 2). The thioether structure is then generated by 1,4-conjugate addition of a Cys onto a dehydro amino acid. As discussed in this review, the manner of dehydration can be quite different, which is one of the criteria for dividing lanthipeptides into different classes. For all lanthipeptides, these linkages are introduced by a post-translational modification process that first involves the dehydration of Ser and Thr residues to 2,3-didehydroalanine (Dha) and 2,3-didehydrobutyrine (Dhb) residues, respectively ( Figure 2). The mechanism by which the thioether cross-links are formed is what unifies this family of compounds. (26-34) Lanthipeptide biosynthetic gene clusters are particularly found in the genomes of many genera of Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, and Cyanobacteria. (10) As a result, lanthipeptide derivatives are undergoing therapeutic evaluation (11-25) and have been used for imaging applications. The increase in the number of characterized lanthipeptides as a result of the bacterial genome sequencing projects has led to the realization that their functions are not limited to antimicrobial activities but also include antifungal, (5) morphogenetic, (6, 7) antiviral, (8) antinociceptive, (9) and antiallodynic functions. Although genes encoding homologues of lanthipeptide biosynthetic enzymes are also present in some archaea and in higher eukaryotes including mammals, (3, 4) lanthipeptide detection and isolation is thus far restricted to bacteria. Installation of lanthionine residues is accomplished through enzymatic post-translational modifications on peptide substrates. When incorporated into a peptide chain via both the amino and acid groups, a lanthionine results in a thioether cross-link. (2) A lanthionine is a bis-amino-bis acid in which two alanine residues are linked by a thioether group that connects their β-carbons ( Figure 1). The name lanthipeptide is a short-hand nomenclature for lanthionine-containing peptides, (1) with lanthipeptides having antimicrobial activities historically called lantibiotics. This review focuses on studies published over the past decade that have provided much insight into the mechanisms of the enzymes that carry out the post-translational modifications. After installation of the characteristic thioether cross-links, tailoring enzymes introduce additional post-translational modifications that are unique to each lanthipeptide and that fine-tune their activities and/or stability. The resulting polycyclic peptides have constrained conformations that confer their biological activities. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name. ![]() The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. Lanthipeptides that display antimicrobial activity are called lantibiotics. Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. ![]()
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