College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology, Hangzhou, 310014, China.
Key Laboratory of Marine Ecosystem and Biogeochemistry, Ministry of Natural Resources & Second Institute of Oceanography, Ministry of Natural Resources, Hangzhou, 310012, China.
Microbiome. 2023 Jun 28;11(1):144. doi: 10.1186/s40168-023-01573-3.
Marine prokaryotes are a rich source of novel bioactive secondary metabolites for drug discovery. Recent genome mining studies have revealed their great potential to bio-synthesize novel secondary metabolites. However, the exact biosynthetic chemical space encoded by the marine prokaryotes has yet to be systematically evaluated.
We first investigated the secondary metabolic potential of marine prokaryotes by analyzing the diversity and novelty of the biosynthetic gene clusters (BGCs) in 7541 prokaryotic genomes from cultivated and single cells, along with 26,363 newly assembled medium-to-high-quality genomes from marine environmental samples. To quantitatively evaluate the unexplored biosynthetic chemical space of marine prokaryotes, the clustering thresholds for constructing the biosynthetic gene cluster and molecular networks were optimized to reach a similar level of the chemical similarity between the gene cluster family (GCF)-encoded metabolites and molecular family (MF) scaffolds using the MIBiG database. The global genome mining analysis demonstrated that the predicted 70,011 BGCs were organized into 24,536 mostly new (99.5%) GCFs, while the reported marine prokaryotic natural products were only classified into 778 MFs at the optimized clustering thresholds. The number of MF scaffolds is only 3.2% of the number of GCF-encoded scaffolds, suggesting that at least 96.8% of the secondary metabolic potential in marine prokaryotes is untapped. The unexplored biosynthetic chemical space of marine prokaryotes was illustrated by the 88 potential novel antimicrobial peptides encoded by ribosomally synthesized and post-translationally modified peptide BGCs. Furthermore, a sea-water-derived Aquimarina strain was selected to illustrate the diverse biosynthetic chemical space through untargeted metabolomics and genomics approaches, which identified the potential biosynthetic pathways of a group of novel polyketides and two known compounds (didemnilactone B and macrolactin A 15-ketone).
The present bioinformatics and cheminformatics analyses highlight the promising potential to explore the biosynthetic chemical diversity of marine prokaryotes and provide valuable knowledge for the targeted discovery and biosynthesis of novel marine prokaryotic natural products. Video Abstract.
海洋原核生物是发现药物的新型生物活性次生代谢物的丰富来源。最近的基因组挖掘研究表明，它们具有生物合成新型次生代谢物的巨大潜力。然而，海洋原核生物所编码的准确生物合成化学空间尚未得到系统评估。
我们首先通过分析培养和单细胞的 7541 个原核基因组以及 26363 个新组装的海洋环境样本中的中等至高质量基因组中的生物合成基因簇（BGC）的多样性和新颖性，来研究海洋原核生物的次生代谢潜力。为了定量评估海洋原核生物未被探索的生物合成化学空间，优化了构建生物合成基因簇和分子网络的聚类阈值，以达到使用 MIBiG 数据库在基因簇家族（GCF）编码代谢物和分子家族（MF）支架之间的化学相似性的相似水平。全球基因组挖掘分析表明，预测的 70011 BGC 被组织成 24536 个主要新的（99.5%）GCF，而报道的海洋原核天然产物仅在优化聚类阈值下被分类为 778 MF。MF 支架的数量仅为 GCF 编码支架数量的 3.2%，这表明海洋原核生物至少 96.8%的次生代谢潜力尚未被开发。通过核糖体合成和翻译后修饰肽 BGC 编码的 88 种潜在新型抗菌肽说明了海洋原核生物未被探索的生物合成化学空间。此外，通过非靶向代谢组学和基因组学方法选择了一株来自海水的 Aquimarina 菌株来说明多样化的生物合成化学空间，鉴定了一组新型聚酮类化合物和两种已知化合物（didemnilactone B 和 macrolactin A 15-ketone）的潜在生物合成途径。
本生物信息学和化学信息学分析突出了探索海洋原核生物生物合成化学多样性的巨大潜力，并为靶向发现和合成新型海洋原核天然产物提供了有价值的知识。视频摘要。
