Abstract
Natural products (NPs) are a major source of compounds for medical, agricultural, and biotechnological industries. Many of these compounds are of microbial origin, and, in particular, from Actinobacteria or filamentous fungi. To successfully identify novel compounds that correlate to a bioactivity of interest, or discover new enzymes with desired functions, systematic multiomics approaches have been developed over the years. Bioinformatics tools harness the rapidly expanding wealth of genome sequence information, revealing previously unsuspected biosynthetic diversity. Varying growth conditions or application of elicitors are applied to activate cryptic biosynthetic gene clusters, and metabolomics provide detailed insights into the NPs they specify. Combining these technologies with proteomics‐based approaches to profile the biosynthetic enzymes provides scientists with insights into the full biosynthetic potential of microorganisms. The proteomics approaches include enrichment strategies such as employing activity‐based probes designed by chemical biology, as well as unbiased (quantitative) proteomics methods. In this review, the opportunities and challenges in microbial NP research are discussed, and, in particular, the application of proteomics to link biosynthetic enzymes to the molecules they produce, and vice versa.
Highlights
Natural products (NPs) are a major source of compounds for medical, bial resistance means that bacterial infecagricultural, and biotechnological industries
Before we turn to proteomics-based approaches in NP discovery, we first highlight metabolomics technologies that are crucial in building innovative systems biology-based discovery pipelines
An element commonly found in the NP-synthetic machinery is the carrier protein (CP) domain, which acts as an anchor for tethering biosynthetic intermediates in polyketide synthases (PKS), non-ribosomal peptide synthases (NRPS), and fatty acid synthase (FAS) systems.[52]
Summary
In the later part of the twentieth century, mutational analysis combined with emerging DNA sequencing technologies allowed scientists to start to map known NPs to their corresponding BGCs, and to elucidate the biosynthetic logic. Biochemists and bioinformaticists are working closely together to develop efficient dereplication pipelines, aiming at finding new chemical structures Such efforts include finding “oddly” structured gene clusters, in other words BGCs that either contain rare or unknown biosynthetic genes or have unexpected combinations of known genes. The MIBiG (minimum information about a biosynthetic gene cluster) database is an important new community-based resource that is used for dereplication purposes in genome-mining tools like antiSMASH.[19] Except connecting BGCs to their chemical potential and environmental diversity, MIBiG is built to provide guidance in gene cluster engineering.[24] despite all the spectacular developments in the genome-mining technologies, there is still a tremendous amount of work to do in order to identify new molecules at a high frequency and put them into use
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