Divergent Evolution of Lanthipeptide Stereochemistry

The three-dimensional structure of natural products is
critical
for their biological activities and, as such, enzymes have evolved
that specifically generate active stereoisomers. Lanthipeptides are
post-translationally modified peptidic natural products that contain
macrocyclic thioethers featuring lanthionine (Lan) and/or methyllanthionine
(MeLan) residues with defined stereochemistry. In this report, we
compare two class I lanthipeptide biosynthetic gene clusters (BGCs), coi and olv, that represent two families
of lanthipeptide gene clusters found in Actinobacteria. The precursor
peptides and BGCs are quite similar with genes encoding a dehydratase,
cyclase, and methyltransferase (MT). We illustrate that the precursor
peptide CoiA1 is converted by these enzymes into a polymacrocyclic
product, mCoiA1, that contains an analogous ring pattern to the previously
characterized post-translationally modified OlvA peptide (mOlvA).
However, a clear distinction between the two BGCs is an additional
Thr-glutamyl lyase (GL) domain that is fused to the MT, CoiSA, which results in divergence of the product stereochemistry for
the coi BGC. Two out of three MeLan rings of mCoiA1
contain different stereochemistry than the corresponding residues
in mOlvA, with the most notable difference being a rare d-allo-l-MeLan residue, the formation of
which is guided by CoiSA. This study illustrates how nature
utilizes a distinct GL to control natural product stereochemistry
in lanthipeptide biosynthesis.