ja9b12736_si_001.pdf (3.44 MB)
Oxidative Carbon Backbone Rearrangement in Rishirilide Biosynthesis
journal contribution
posted on 2020-03-19, 18:46 authored by Olga Tsypik, Roman Makitrynskyy, Britta Frensch, David L. Zechel, Thomas Paululat, Robin Teufel, Andreas BechtholdThe
structural diversity of type II polyketides is largely generated
by tailoring enzymes. In rishirilide biosynthesis by Streptomyces
bottropensis, 13C-labeling studies previously
implied extraordinary carbon backbone and side-chain rearrangements.
In this work, we employ gene deletion experiments and in vitro enzyme studies to identify key biosynthetic intermediates and expose
intricate redox tailoring steps for the formation of rishirilides
A, B, and D and lupinacidin A. First, the flavin-dependent RslO5 reductively
ring-opens the epoxide moiety of an advanced polycyclic intermediate
to form an alcohol. Flavin monooxygenase RslO9 then oxidatively rearranges
the carbon backbone, presumably via lactone-forming Baeyer–Villiger
oxidation and subsequent intramolecular aldol condensation. While
RslO9 can further convert the rearranged intermediate to rishirilide
D and lupinacidin A, an additional ketoreductase RslO8 is required
for formation of the main products rishirilide A and rishirilide B.
This work provides insight into the structural diversification of
aromatic polyketide natural products via unusual redox tailoring reactions
that appear to defy biosynthetic logic.