Characterization of α-ketoglutarate-dependent dioxygenase FtmF catalyzing endoperoxide bond formation in fumitremorgin pathway

Highly complex structure is one of the characteristics of natural products, and often related to their potent and specific biological activities. The discovery of enzymes that decorate the structures of natural products is important to expand their structural diversity. Verruculogen possessing an endoperoxide bond in its structure is one of the end products of the fumitremorgin biosynthetic pathway in a human pathogen, Aspergillus fumigatus (Kato N., et al. 2009 ChemBioChem, 10: 920-928). The biosynthesis of verruculogen involves multiple oxidation processes, and the last one is the formation of an endoperoxide bond between two isoprene moieties of verruculogen. Our genetic and biochemical analyses demonstrated that α-ketoglutarate (KG)-dependent dioxygenase FtmF is responsible for the endoperoxide bond formation of verruculogen in A. fumigatus (Kato N., et al. 2011 ChemBioChem, 12: 711-714). Despite growing interest in the chemistry of endoperoxide bond formation, only 2 enzymes, FtmF and cyclooxygenase involved in the prostaglandin biosynthesis, have been reported as an endoperoxidation catalyst. To understand the molecular basis of the FtmF-mediated endoperoxidation, we performed structural analysis of FtmF. Crystal structure of FtmF was determined at 1.8 Å resolution. FtmF forms a dimeric structure in the crystal and adopts a double-stranded β-helix fold, which is common to all the non-heme Fe^II/α-KG-dependent oxygenases. The result of docking simulation of FtmF and its substrate fumitremorgin B and possible reaction mechanism of FtmF will be presented.