Abstract
BackgroundAmong naturally occurring small molecules, tRNA-derived cyclodipeptides are a class that have attracted attention for their diverse and desirable biological activities. However, no tools are available to link cyclodipeptide synthases identified within prokaryotic genome sequences to their chemical products. Consequently, it is unclear how many genetically encoded cyclodipeptides represent novel products, and which producing organisms should be targeted for discovery.ResultsWe developed a pipeline for identification and classification of cyclodipeptide biosynthetic gene clusters and prediction of aminoacyl-tRNA substrates and complete chemical structures. We leveraged this tool to conduct a global analysis of tRNA-derived cyclodipeptide biosynthesis in 93,107 prokaryotic genomes, and compared predicted cyclodipeptides to known cyclodipeptide synthase products and all known chemically characterized cyclodipeptides. By integrating predicted chemical structures and gene cluster architectures, we created a unified map of known and unknown genetically encoded cyclodipeptides.ConclusionsOur analysis suggests that sizeable regions of the chemical space encoded within sequenced prokaryotic genomes remain unexplored. Our map of the landscape of genetically encoded cyclodipeptides provides candidates for targeted discovery of novel compounds. The integration of our pipeline into a user-friendly web application provides a resource for further discovery of cyclodipeptides in newly sequenced prokaryotic genomes.
Highlights
Among naturally occurring small molecules, tRNA-derived cyclodipeptides are a class that have attracted attention for their diverse and desirable biological activities
The few cyclodipeptides known to be biosynthesized via cyclodipeptide synthases (CDPSs)-dependent routes are noted for their antibacterial activities, while pulcherriminic acid is an iron chelating agent, and mycocyclosin may be essential for Mycobacterium tuberculosis activity [4]
Genomic prediction of cyclodipeptide synthase products We developed an algorithm to identify CDPSs, classify their subfamilies, identify active sites and predict their aminoacyl-tRNA substrates, and predict the final chemical structures of their corresponding products (Fig. 1, Methods)
Summary
Among naturally occurring small molecules, tRNA-derived cyclodipeptides are a class that have attracted attention for their diverse and desirable biological activities. The privileged scaffolds of these compounds have been optimized by evolution for targeted interactions with biological macromolecules, in order to provide a fitness advantage for their producers [2] As a result, they represent the basis for the majority small molecule drugs currently in clinical use [1]. A class of natural products that have attracted considerable interest in recent years for their bioactivities are the cyclodipeptides [3] The scaffolds of these compounds can be accessed either by nonribosomal peptide synthases (NRPSs), or alternatively via cyclodipeptide synthases (CDPSs) [4]. Both classes of enzymes are typically located within a cluster of genes involved in the biosynthesis and tailoring of the cyclodipeptide product [5]. Bioactive cyclodipeptides include the antibiotic bicyclomicin, used as a food additive to prevent diarrhea in livestock [9], the cytotoxic agent neihumicin [10], and the immunosuppressive agent gliotoxin [11], as well as other
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