Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products
Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products
复制标题
DOI：
10.1038/nature03668
复制
发表时间：
2005-06-16
期刊：
影响因子：
64.8
通讯作者：
Richard, SB
中科院分区：
文献类型：
--
作者：
Kuzuyama, T;Noel, JP;Richard, SB
抗氧化剂萘特平是一种天然产物，它含有一个以多酮类化合物为基础的芳香族核心，并附有一个来自异戊二烯（萜烯）代谢的 10 碳香叶基（1-3）。混合天然产物（如萘特品）含有 5 碳（二甲基烯丙基）、10 碳（香叶基）或 15 碳（法呢基）异戊烯链，具有不同于非异戊二烯化芳香族前体的生物活性（4）。这些混合天然产物代表了新的抗微生物、抗氧化、抗炎、抗病毒和抗癌化合物。少数负责芳香族前炔基团附着的芳香族前炔基转移酶（PTases）最近才被分离和鉴定出来（5,6）。在此，我们报告了一种结构新颖的芳香族 PT 酶--来自链霉菌 CL190 菌株的 Orf2 的基因鉴定、生化表征和高分辨率 X 射线晶体结构，并结合了底物和底物类似物。在体内，Orf2 在萘素的生物合成过程中将一个香叶基团连接到 1,3,6,8-四羟基萘衍生的多酮上。在体外，Orf2 可催化合成、微生物和植物来源的各种含羟基芳香受体的碳-碳基和碳-氧基预炔化作用。这些晶体结构与体外检测相结合，为我们了解并有可能利用这一结构独特的芳香族 PT 酶家族操纵芳香族小分子的区域特异性预炔化奠定了基础。
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.