title: Cytochrome P450 as dimerization catalyst in diketopiperazine alkaloid biosynthesis.
abstract: As dimeric natural products frequently exhibit useful biological activities, identifying and understanding their mechanisms of dimerization is of great interest. One such compound is (−)-ditryptophenaline, isolated from Aspergillus flavus, which inhibits substance P receptor for potential analgesic and anti-inflammatory activity. Through targeted gene knockout in A. flavus and heterologous yeast gene expression, we determined for the first time the gene cluster and pathway for the biosynthesis of a dimeric diketopiperazine alkaloid. We also determined that a single cytochrome P450, DtpC, is responsible not only for pyrroloindole ring formation but also for concurrent dimerization of N-methylphenylalanyltryptophanyl diketopiperazine monomers into a homodimeric product. Furthermore, DtpC exhibits relaxed substrate specificity, allowing the formation of two new dimeric compounds from a non-native monomeric precursor, brevianamide F. A radical-mediated mechanism of dimerization is proposed.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Saruwatari
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Yagishita
authors.forename: Takashi
authors.initials: T
authors.lastname: Mino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Kinya
authors.initials: K
authors.lastname: Hotta
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001231:Aspergillus flavus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism; D053898:Biosynthetic Pathways; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D054659:Diketopiperazines / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005810:Multigene Family
chemical_list: D000470:Alkaloids; D001688:Biological Products; D054659:Diketopiperazines; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System