posted on 2016-04-18, 00:00authored bySwapnil
V. Ghodge, Kristen A. Biernat, Sarah Jane Bassett, Matthew R. Redinbo, Albert A. Bowers
Pantocin A (PA) is
a member of the growing family of ribosomally
encoded and post-translationally modified peptide natural products
(RiPPs). PA is much smaller than most known RiPPs, a tripeptide with
a tight bicyclic core that appears to be cleaved from the middle of
a larger 30-residue precursor peptide. We show here that the enzyme
PaaA catalyzes the double dehydration and decarboxylation of two glutamic
acid residues in the 30-residue precursor PaaP. Further truncates
of PaaP leader and follower peptide sequences demonstrate the different
impacts of these two regions on PaaA-mediated tailoring and delineate
an essential role for the follower sequence in the decarboxylation
step. The crystal structure of apo PaaA is reported,
allowing identification of structural features that set PaaA apart
from other homologous enzymes that typically do not catalyze such
extended post-translational chemistry. Together, these data reveal
how additional chemistry can be extracted from a ubiquitous enzyme
family toward ribosomally derived peptide natural product biosynthesis
and suggest that more examples of such enzymes likely exist in untapped
genomic space.