Molecular Basis for the Final Oxidative Rearrangement Steps in Chartreusin Biosynthesis

Oxidative
rearrangements play key roles in introducing structural
complexity and biological activities of natural products biosynthesized
by type II polyketide synthases (PKSs). Chartreusin (1) is a potent antitumor polyketide that contains a unique rearranged
pentacyclic aromatic bilactone aglycone derived from a type II PKS.
Herein, we report an unprecedented dioxygenase, ChaP, that catalyzes
the final α-pyrone ring formation in 1 biosynthesis
using flavin-activated oxygen as an oxidant. The X-ray crystal structures
of ChaP and two homologues, docking studies, and site-directed mutagenesis
provided insights into the molecular basis of the oxidative rearrangement
that involves two successive C–C bond cleavage steps followed
by lactonization. ChaP is the first example of a dioxygenase that
requires a flavin-activated oxygen as a substrate despite lacking
flavin binding sites, and represents a new class in the vicinal oxygen
chelate enzyme superfamily.