Ribosomal natural products from the human oral microbiome

该项目涉及人类口腔微生物的新天然产物的表征在人类微生物组的调查和表征过程中，对许多细菌基因组进行了测序。在寻找新的天然产物的基因簇的过程中，在放线菌目的两个成员的基因组中，（lantipeptides，lasso peptides，linaridins）。推定的lasso peptide基因簇显示出不寻常的特征：多达12种，但至少5种前体肽彼此相邻编码，邻近加工酶，天冬酰胺合成酶。因此，这种酶似乎具有很大的底物混杂性。在这个项目的过程中，尽可能多的多达17个预测的天然产物应被表征，并阐明其结构。这应该首先用质谱方法如Nano-DESI-MS来完成。摩尔和多瑞斯坦实验室在结合生物信息学方法的基于质谱的肽表征方面有很多经验。感兴趣的候选物应该针对不同的生物靶标进行测试，并且应该用NMR光谱法充分阐明它们的结构。此外，还应进一步研究其杂合性，开发其杂合性，以合成新的非天然产物。该项目的另一部分涉及人类口腔微生物组细菌共生的表征：细菌菌株的代谢相互作用应通过共培养和随后的MALDI成像质谱和分子网络分析来阐明。此外，应系统地搜索口腔微生物组的更多测序基因组，以进一步寻找天然产物基因簇和可能缺失的初级代谢生物合成途径，以进一步表征共生体。

The project deals with the characterization of new natural products from the human oral microbiomeDuring the survey and characterization of the human microbiome a lot of bacterial genomes were sequenced. In the search for gene clusters for new natural products, in two genomes of members of the actinomycetales, several gene clusters encoding for different ribosomal synthezised natural products (lantipeptides, lasso peptides, linaridins) were found. The putative lasso peptide gene cluster shows unusual features: Up to twelve, but at least five precursor peptides are encoded next to each other, adjacent to a processing enzyme, an asparagine synthetase. This enzyme thus seems to have a great substrate promiscuity. In the course of this project, as many as possible of the up to 17 predicted natural products should be characterized and their structure elucidated. This should be done initially with mass spectrometric methods as Nano-DESI-MS. The Moore and Dorrestein labs have lots of experience with the mass-spectrometry based characterization of peptides combined with bioinformatic methods. Interesting candidates should be tested against different biological targets and their structure should be fully elucidated with NMR spectroscopy. Additionally, the putatively promiscuous asparagine synthetase should be further characterized and the promiscuity should be exploited, to synthesize new unnatural natural products. Another part of the project deals with the characterization of the symbioses of the human oral microbiome bacteria: The metabolic interactions of bacterial strains should be elucidated by cocultivations and subsequent MALDI imaging mass spectrometry and molecular networking analysis. Additionally, more of the sequenced genomes of the oral microbiome should be searched systematically for further natural product gene clusters and possibly missing biosynthetic pathways from the primary metabolism to further characterize the symbioses.