Abstract
Cyclodipeptide synthases (CDPSs) use as substrates two amino acids activated as aminoacyl-tRNAs to synthesize cyclodipeptides in secondary metabolites biosynthetic pathways. Since the first description of a CDPS in 2002, the number of putative CDPSs in databases has increased exponentially, reaching around 800 in June 2017. They are likely to be involved in numerous biosynthetic pathways but the diversity of their products is still under-explored. Here, we describe the activity of 32 new CDPSs, bringing the number of experimentally characterized CDPSs to about 100. We detect 16 new cyclodipeptides, one of which containing an arginine which has never been observed previously. This brings to 75 the number of cyclodipeptides formed by CDPSs out of the possible 210 natural ones. We also identify several consensus sequences related to the synthesis of a specific cyclodipeptide, improving the predictive model of CDPS specificity. The improved prediction method enables to propose the main product synthesized for about 80% of the CDPS sequences available in databases and opens the way for the deciphering of CDPS-dependent pathways. Analysis of phylum distribution and predicted activity for all CDPSs identified in databases shows that the experimentally characterized set is representative of the whole family. Our work also demonstrates that some cyclodipeptides, precursors of diketopiperazines with interesting pharmacological properties and previously described as being synthesized by fungal non-ribosomal peptide synthetases, can also be produced by CDPSs in bacteria.
Highlights
Cyclodipeptide synthases (CDPSs) are a novel family of enzymes that use aminoacyl-tRNAs as substrates for the biosynthesis of various cyclodipeptides (Gondry et al, 2009; Moutiez et al, 2017), precursors of diketopiperazines (DKPs), a large class of natural products with noteworthy biological activities (Borthwick, 2012)
We investigated the production of cyclodipeptides of 42 selected sequences (Supplemental Data Set 1)
Among the 27 unpredictable NYH members selected, ten (CDPSs 62-66, 68-71, 103) had been put into the putative specificity-group containing AlbC by Jacques et al, suggesting that the main cyclodipeptide they synthesize is a phenylalanyl-containing cyclodipeptide, named cFX (Jacques et al, 2015)
Summary
Cyclodipeptide synthases (CDPSs) are a novel family of enzymes that use aminoacyl-tRNAs (aa-tRNAs) as substrates for the biosynthesis of various cyclodipeptides (Gondry et al, 2009; Moutiez et al, 2017), precursors of diketopiperazines (DKPs), a large class of natural products with noteworthy biological activities (Borthwick, 2012). The NYH enzymes have been extensively characterized and the crystal structures of three of them, AlbC from Streptomyces noursei, Rv2275 from Mycobacterium tuberculosis and YvmC from Bacillus licheniformis, are available (Vetting et al, 2010; Bonnefond et al, 2011; Sauguet et al, 2011; Moutiez et al, 2014a). These CDPSs adopt a common architecture with a monomer containing a Rossmann-fold domain. The dipeptidyl moiety undergoes an intramolecular cyclization leading to the final cyclodipeptide
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