title: Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products.
abstract: 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. 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. 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. 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.
authors.affiliation: Jack Skirball Chemical Biology and Proteomics Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Kuzuyama
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Noel
authors.forename: Stéphane B
authors.initials: SB
authors.lastname: Richard
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D001688:Biological Products / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004122:Dimethylallyltranstransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005798:Genes, Bacterial / Q000235:genetics; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011487:Protein Conformation; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D000975:Antioxidants; D001688:Biological Products; D009285:Naphthoquinones; C064496:naphterpin; D004122:Dimethylallyltranstransferase; D008274:Magnesium