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Unprecedented Cyclization Catalyzed by a Cytochrome P450 in Benzastatin Biosynthesis
journal contribution
posted on 2018-05-02, 00:00 authored by Hayama Tsutsumi, Yohei Katsuyama, Miho Izumikawa, Motoki Takagi, Manabu Fujie, Noriyuki Satoh, Kazuo Shin-ya, Yasuo OhnishiBenzastatins
have unique structures probably derived from geranylated p-aminobenzoic acids. The indoline and tetrahydroquinoline
scaffolds are presumably formed by cyclization of the geranyl moiety,
but the cyclization mechanism was unknown. We studied the benzastatin
biosynthetic gene cluster of Streptomyces sp. RI18;
functions of the six enzymes encoded by it were analyzed by gene disruption
in a heterologous host and in vitro enzyme assays. We propose the
biosynthetic pathway for benzastatins in which a cytochrome P450 (BezE)
is responsible for the cyclization of geranylated p-acetoxyaminobenzoic acids; BezE catalyzes elimination of acetic
acid to form an iron nitrenoid, nitrene transfer to form an aziridine
ring, and nucleophilic addition of hydroxide ion to C-10 and chloride
ion to C-9 to generate the indoline and tetrahydroquinoline scaffolds,
respectively. Discovery of this enzyme, which should be termed cytochrome
P450 nitrene transferase, provides an important insight into the functional
diversity of cytochrome P450.