Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products

Article

关键词: FARNESYL DIPHOSPHATE SYNTHASE;    CRYSTAL-STRUCTURE;    PROTEIN FARNESYLTRANSFERASE;    POLYKETIDE SYNTHASE;    BINDING PROTEIN;    RESOLUTION;    PRENYLTRANSFERASE;    IDENTIFICATION;    MECHANISM;    ENZYMES;   

DOI  :  10.1038/nature03668

来源: SCIE

【 摘 要 】

The anti-oxidant naphterpin is a natural product containing a polyketide-based aromatic core with an attached 10-carbon geranyl group derived from isoprenoid ( terpene) metabolism(1-3). Hybrid natural products such as naphterpin that contain 5-carbon ( dimethylallyl), 10-carbon ( geranyl) or 15-carbon ( farnesyl) isoprenoid chains possess biological activities distinct from their non-prenylated aromatic precursors(4). These hybrid natural products represent new anti-microbial, anti-oxidant, anti-inflammatory, anti-viral and anti-cancer compounds. A small number of aromatic prenyltransferases (PTases) responsible for prenyl group attachment have only recently been isolated and characterized(5,6). Here we report the gene identification, biochemical characterization and high-resolution X-ray crystal structures of an architecturally novel aromatic PTase, Orf2 from Streptomyces sp. strain CL190, with substrates and substrate analogues bound. In vivo, Orf2 attaches a geranyl group to a 1,3,6,8-tetrahydroxynaphthalene-derived polyketide during naphterpin biosynthesis. In vitro, Orf2 catalyses carbon-carbon-based and carbon-oxygen-based prenylation of a diverse collection of hydroxyl-containing aromatic acceptors of synthetic, microbial and plant origin. These crystal structures, coupled with in vitro assays, provide a basis for understanding and potentially manipulating the regio-specific prenylation of aromatic small molecules using this structurally unique family of aromatic PTases.

【 授权许可】

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