title: Uncovering the unusual D-ring construction in terretonin biosynthesis by collaboration of a multifunctional cytochrome P450 and a unique isomerase.
abstract: Terretonin (1) is a fungal meroterpenoid isolated from Aspergillus terreus, and possesses a highly oxygenated and unique tetracyclic structure. Although the biosynthetic gene cluster for 1 has been identified and the biosynthesis has recently been studied by heterologous reconstitution and targeted-gene deletion experiments, the last few steps of the terretonin pathway after terrenoid (6) have yet to be elucidated. Notably, the mechanism for the D-ring expansion to afford the terretonin scaffold has been a long-standing mystery to solve. Here we report the characterization of three enzymes that convert 6 into 1, as well as the complete biosynthetic pathway of 1. In the proposed terretonin pathway, the cytochrome P450 Trt6 catalyzes three successive oxidations to transform 6 into an unstable intermediate, which then undergoes the D-ring expansion and unusual rearrangement of the methoxy group to afford the core skeleton of 1. This unprecedented rearrangement is catalyzed by a novel isomerase Trt14. Finally, the nonheme iron-dependent dioxygenase Trt7 accomplishes the last two oxidation reactions steps to complete the biosynthesis.
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Yudai
authors: Y
authors: Matsuda
authors: Taiki
authors: T
authors: Iwabuchi
authors: Toshiyuki
authors: T
authors: Wakimoto
authors: Takayoshi
authors: T
authors: Awakawa
authors: Ikuro
authors: I
authors: Abe
mesh_terms: D001230:Aspergillus / Q000235:genetics / Q000378:metabolism*; D001236:Aspergillus oryzae / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D007535:Isomerases / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005656:Fungal Proteins; D013729:Terpenes; C543992:terretonin E; D003577:Cytochrome P-450 Enzyme System; D007535:Isomerases