Abstract
The rational discovery of new specialized metabolites by genome mining represents a very promising strategy in the quest for new bioactive molecules. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural product that derive from genetically encoded precursor peptides. However, RiPP gene clusters are particularly refractory to reliable bioinformatic predictions due to the absence of a common biosynthetic feature across all pathways. Here, we describe RiPPER, a new tool for the family-independent identification of RiPP precursor peptides and apply this methodology to search for novel thioamidated RiPPs in Actinobacteria. Until now, thioamidation was believed to be a rare post-translational modification, which is catalyzed by a pair of proteins (YcaO and TfuA) in Archaea. In Actinobacteria, the thioviridamide-like molecules are a family of cytotoxic RiPPs that feature multiple thioamides, which are proposed to be introduced by YcaO-TfuA proteins. Using RiPPER, we show that previously undescribed RiPP gene clusters encoding YcaO and TfuA proteins are widespread in Actinobacteria and encode a highly diverse landscape of precursor peptides that are predicted to make thioamidated RiPPs. To illustrate this strategy, we describe the first rational discovery of a new structural class of thioamidated natural products, the thiovarsolins from Streptomyces varsoviensis.
Highlights
Microorganisms have provided humankind with a vast plethora of specialized metabolites with invaluable applications in medicine and agriculture.[1]
A progressive trimming process determined that a cluster of seven genes that are conserved across the Nocardiopsis and Streptomyces biosynthetic gene clusters (BGCs) was sufficient for compound production: varA, varY, varT, varO, varL, varP and varS
The discovery of the thiovarsolins supports the existence of an unexplored array of thioamidated Ribosomally synthesized and post-translationally modified peptides (RiPPs) in Actinobacteria
Summary
Microorganisms have provided humankind with a vast plethora of specialized metabolites with invaluable applications in medicine and agriculture.[1]. Among the main classes of specialized metabolites produced by microorganisms, the ribosomally synthesized and posttranslationally modified peptides[4] (RiPPs) may harbor the largest amount of unexplored structural diversity RiPP BGCs can be identified by the co-occurrence of specific RiPP tailoring enzymes (RTEs) alongside a precursor peptide that contains sequence motifs that are characteristic of a given RiPP family This makes it relatively simple to identify further examples of known RiPP families,[5,6] but the identification of currently undiscovered RiPP families remains a significant unsolved problem. This analysis informed the discovery of the thioamidated thiovarsolins from Streptomyces varsoviensis, which are predicted to belong to a wider family of related thioamidated RiPPs and represents the first rational discovery of a new family of thioamidated compounds from nature
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