Homologous NRPS-like gene clusters mediate redundant small-molecule biosynthesis in Aspergillus flavus.
Homologous NRPS-like gene clusters mediate redundant small-molecule biosynthesis in Aspergillus flavus.
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DOI：
10.1002/anie.201207456
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发表时间：
2013-01-28
影响因子：
16.6
通讯作者：
Keller, Nancy P.
中科院分区：
文献类型：
--
作者：
Forseth, Ry R.;Amaike, Saori;Schwenk, Daniel;Affeldt, Katharyn J.;Hoffmeister, Dirk;Schroeder, Frank C.;Keller, Nancy P.
真菌是植物相关天然产物的最丰富来源之一。[1]真菌小分子的这种巨大多样性在真菌生态学中发挥重要作用，例如作为毒力因子和化学防御剂。然而，只有一小部分的基因组分析所建议的生物合成能力已被观察到在实验室条件下，因为许多，也许甚至大多数生物合成途径的表达强烈依赖于环境条件。[2]在这里，我们展示了使用比较代谢组学[3]来分析敲除、过表达和敲低菌株，以鉴定来自产黄曲霉毒素的子囊菌黄曲霉中的两个非核糖体肽合成酶（NRPS）基因簇的代谢物，黄曲霉是一种农作物污染物[4]和导致免疫功能低下的人类曲霉病的机会致病菌。[5] A.黄曲霉基因组编码至少25个聚酮合酶（PKS），18个NRPS和两个杂合NRPS-PKS基因簇，[6]仅对四种代谢物进行了分配。[7]许多A.黄曲霉次级代谢途径受核蛋白LaeA控制，LaeA是黄曲霉形态发生和毒力因子的全局调节因子。黄曲霉和其他病原真菌。[8]两个LaeA调节的簇，命名为lna和lnb，表现出惊人的遗传相似性水平（图1a，表S1）。lna和lnb簇分别含有两个具有高序列同源性（在氨基酸水平上58%相同）的非典型NRPS基因，lnaA和lnbA，其伴随有可能编码定制酶的匹配基因组。lna和lnb是孤儿簇，没有已知的相关代谢物，属于非典型NRPS基因家族，其由腺苷酸化（A）结构域、肽基和羧基组成。
Fungi are among the most prolific sources of pharmacologically relevant natural products.[1] This large diversity of fungal small molecules serves important functions in fungal ecology, for example as virulence factors and as chemical defense agents. However, only a fraction of the biosynthetic capabilities suggested by genomic analyses has been observed under laboratory conditions, because expression of many, perhaps even most biosynthetic pathways depends strongly on environmental conditions.[2] Here we demonstrate the use of comparative metabolomics [3] for the analysis of knock-out, overexpression, and knock-down strains to identify metabolites derived from two nonribosomal peptide synthetase (NRPS) gene clusters in the aflatoxin-producing ascomycete Aspergillus flavus, a crop contaminant [4] and opportunistic pathogen that causes aspergillosis in immunocompromised humans.[5]Although the A. flavus genome encodes at least 25 polyketide synthase (PKS), 18 NRPS, and two hybrid NRPS-PKS gene clusters,[6] assignments have been made for only four metabolites.[7] Many A. flavus secondary-metabolite pathways are under the control of the nuclear protein LaeA, a global regulator of morphogenesis and virulence factor in A. flavus and other pathogenic fungi.[8] Two LaeA-regulated clusters, which were named lna and lnb, exhibit a striking level of genetic similarity (Figure 1a, Table S1). The lna and lnb clusters contain two noncanonical NRPS genes with high sequence homology (58% identical at the amino acid level), lnaA and lnbA, respectively, which are accompanied by matching sets of genes likely coding for tailoring enzymes. lna and lnb are orphan clusters that have no known associated metabolites and belong to a family of noncanonical NRPS genes that consist of an adenylation (A) domain, a peptidyl
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影响因子：
15
作者：
BOGER, DL;ZHOU, JC
通讯作者：
ZHOU, JC
影响因子：
15
作者：
Forseth, Ry R.;Fox, Ellen M.;Chung, DaWoon;Howlett, Barbara J.;Keller, Nancy P.;Schroeder, Frank C.
通讯作者：
Schroeder, Frank C.
影响因子：
3.2
作者：
Andrianopoulos, A;Kourambas, S;Hynes, MJ
通讯作者：
Hynes, MJ
影响因子：
3.8
作者：
AYER, WA;SINGER, PP
通讯作者：
SINGER, PP
影响因子：
14.8
作者：
Bergmann, Sebastian;Schuemann, Julia;Hertweck, Christian
通讯作者：
Hertweck, Christian