Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products.
Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products.
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DOI：
10.1016/j.fgb.2016.01.012
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Charkoudian LK
中科院分区：
文献类型：
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作者：
Li YF;Tsai KJS;Harvey CJB;Li JJ;Ary BE;Berlew EE;Boehman BL;Findley DM;Friant AG;Gardner CA;Gould MP;Ha JH;Lilley BK;McKinstry EL;Nawal S;Parry RC;Rothchild KW;Silbert SD;Tentilucci MD;Thurston AM;Wai RB;Yoon Y;Aiyar RS;Medema MH;Hillenmeyer ME;Charkoudian LK
微生物产生多种具有临床和农业相关生物活性的天然产物。在细菌和真菌中，编码生物合成途径中连续步骤的基因往往作为生物合成基因簇(BGC)聚集在染色体上。从历史上看，“活动导向”的NP发现方法侧重于对可培养微生物产生的NP进行生物活性筛选。相比之下，最近的“基因组挖掘”方法首先确定候选的BGC，使用合成生物学方法表达这些生物合成基因，最后测试NPs的生产。然而，由于缺乏编码实验验证产物的BGC的全面目录，真菌基因组挖掘工作和对新序列和NP空间的探索受到限制。在这项研究中，我们生成了一个全面的真菌NPs参考集，其生物合成基因簇在已发表的文献中进行了描述。为了生成这个数据集，我们首先确定了包括同行评审文章和相关核苷酸记录的NCBI记录。我们根据文本和同源标准对这些记录进行筛选，以确定与NP相关的假定文章和BGC。接下来，我们手动整理得到的文章、化学结构和蛋白质序列。得到的目录包含197种独特的NP化合物，涵盖几大类真菌NP，包括多酮类、非核糖体肽、萜类和生物碱。每种化合物发表的文章分布表明，对某些受欢迎的化合物的研究存在偏见，例如黄曲霉毒素。对生物合成基因的系统发育分析表明，真菌中仍有许多化学和酶的多样性有待发现。我们的目录被合并到最近推出的关于生物合成基因簇的最小信息(MIBiG)库中，以创建已知的最大真菌BGC和相关NP集，我们预计这一资源将指导未来的基因组挖掘和合成生物学努力，以发现新的真菌酶和代谢物。
Microorganisms produce a wide range of natural products (NPs) with clinically and agriculturally relevant biological activities. In bacteria and fungi, genes encoding successive steps in a biosynthetic pathway tend to be clustered on the chromosome as biosynthetic gene clusters (BGCs). Historically, “activity-guided” approaches to NP discovery have focused on bioactivity screening of NPs produced by culturable microbes. In contrast, recent “genome mining” approaches first identify candidate BGCs, express these biosynthetic genes using synthetic biology methods, and finally test for the production of NPs. Fungal genome mining efforts and the exploration of novel sequence and NP space are limited, however, by the lack of a comprehensive catalog of BGCs encoding experimentally-validated products. In this study, we generated a comprehensive reference set of fungal NPs whose biosynthetic gene clusters are described in the published literature. To generate this dataset, we first identified NCBI records that included both a peer-reviewed article and an associated nucleotide record. We filtered these records by text and homology criteria to identify putative NP-related articles and BGCs. Next, we manually curated the resulting articles, chemical structures, and protein sequences. The resulting catalog contains 197 unique NP compounds covering several major classes of fungal NPs, including polyketides, non-ribosomal peptides, terpenoids, and alkaloids. The distribution of articles published per compound shows a bias towards the study of certain popular compounds, such as the aflatoxins. Phylogenetic analysis of biosynthetic genes suggests that much chemical and enzymatic diversity remains to be discovered in fungi. Our catalog was incorporated into the recently launched Minimum Information about Biosynthetic Gene cluster (MIBiG) repository to create the largest known set of fungal BGCs and associated NPs, a resource that we anticipate will guide future genome mining and synthetic biology efforts toward discovering novel fungal enzymes and metabolites.