Secondary metabolites are structurally diverse natural products (NPs) and have been used for many medical applications, such as antibiotics, antioxidants and anticancer drugs. Most of them were extracted from microorganisms. However, approximately 99% of microorganisms do not grow under the laboratory conditions. How to investigate secondary metabolites in the native environment becomes a challenge that scientists need to resolve. Traditional approaches to discover NPs highly rely on isolating pure cultures, which are time-consuming and biased toward abundant metabolites. Isolating NPs from the native and complex environment is one of the promising solutions. To achieve this goal, we present a chemical approach to label specific functional group(s) on NPs. Through combining LC-MS and metagenomic analysis, low abundant NPs can be pinpointed for further structure prediction. Here, we synthesized methyl and phenyl hydrazide probes to target phenol group containing structures by the ene-type labeling commonly used in proteomic research, which required the HRP catalyst and hydrogen peroxide. The azido-linker was introduced into our probes for further functionalization through CuAAC click chemistry. After optimization in model tests, we showed that our probes labeled phenol-containing substrates, such as tyrosine (Tyr) and vancomycin (Van), with high efficiency. We found that the labeling ability of the methyl hydrazide probe (MeHyzN3) is better than the phenyl hydrazide probe (PhHyzN3). Fluorophores were clicked on labeled substrates for lowering the spectral noise, while biotin for the enrichment. Our chemoselective method, in conjunction with LC-MS and metagenomic analysis, will facilitate the identification of novel phenol-containing secondary metabolites in the complex environment.

Developing chemoselective probes to label secondary metabolites in metabolome

2019 Spring National Meeting

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