Enzymatic Formation of an Aminovinyl Cysteine Residue in Ribosomal Peptide Natural Products

Abstract

The carboxyl‐terminal (C‐terminal) S‐[(Z)‐2‐aminovinyl]‐cysteine (AviCys) analogs have been identified in four families of ribosomally synthesized and post‐translationally modified peptides (RiPPs): lanthipeptides, linaridins, thioamitides, and lipolanthines. Within identified biosynthetic pathways, a highly reactive enethiol intermediate, formed through an oxidative decarboxylation catalyzed by a LanD‐like flavoprotein, can undergo two types of cyclization: a Michael addition with a dehydroamino acid or a coupling reaction initiated by a radical species. The collaborative actions of LanD‐like proteins with diverse enzymes involved in dehydration, dethiolation or cyclization lead to the construction of structurally distinct peptide natural products with analogous C‐terminal macrocyclic moieties. This concept summarizes existing knowledge regarding biosynthetic pathways of AviCys analogs to emphasize the diversity of biosynthetic mechanisms that paves the way for future genome mining explorations into diverse peptide natural products.

Characterization of a LanC-free pathway for the formation of an ll-MeLan residue and an alloAviMeCys residue in the newly identified class V lanthipeptide triantimycins

“…TAMs share an N-terminal ll -MeLan residue, while TAM A1 also occupies an extra internal ll -Lan and a C-terminal (2 S , 3 R )- S -(( Z )-2-aminovinyl)-3-methyl- d -cysteine ( allo AviMeCys). To our knowledge, the allo AviMeCys residue is stereochemically distinct from the previously reported (2 S , 3 S )-AviMeCys residue in other RiPPs, 6 indicating a different forming process. Gene deletion, heterologous co-expression, and extensive structural elucidation efforts collectively supported that the cyclization step for the ll -MeLan formation occurs spontaneously.…”

“…To our knowledge, the allo AviMeCys residue is stereochemically diverse from the (2 S , 3 S )-AviMeCys residue reported in other RiPPs to date. 6,18 This observation contradicts the long-assumed ‘net’ anti-addition of an enethiol nucleophile to a Z -Dhb residue, which would leave the α-H and β-CH in a cis relative position to produce (2 S , 3 S )-AviMeCys. 3 b…”

“…5 Besides the N-terminal and/or internal lanthionine (Lan) and/or methyl-lanthionine (MeLan) residue(s), they also contain a C-terminal (2 S , 3 S )- S -(( Z )-2-aminovinyl)-3-methyl- d -cysteine ((2 S , 3 S )-AviMeCys) residue which is believed to be critical for bioactivity. 6 mSmoA C is the parent and the sole member to date of the class Vb subgroup. 7 It is constrained in a stapled configuration by 2 overlapping (Me)Lan residues and a C-terminal Lan residue ( Fig.…”