Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis

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Abstract

Radical SAM enzymes are versatile enzymes catalysing chemically challenging reactions. Now, a radical SAM enzyme that post-translationally modifies ribosomally synthesized peptides to contain D-amino acids has been discovered in Bacillus subtilis, and its mechanism has been deciphered. These peptides, called epipeptides, efficiently inhibit bacterial growth.

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An environmental bacterial taxon with a large and distinct metabolic repertoire.

Micheal C Wilson, Tetsushi Mori, Christian Rückert … (2014)

Cultivated bacteria such as actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa containing talented bacteria indeed exist. Here we report the single-cell- and metagenomics-based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chemically and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chemical uniqueness of 'Entotheonella' compounds provide significant opportunities for ecological studies and drug discovery.

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The Radical SAM Superfamily.

Perry A Frey, Adrian D. Hegeman, Frank J Ruzicka (2015)

The radical S-adenosylmethionine (SAM) superfamily currently comprises more than 2800 proteins with the amino acid sequence motif CxxxCxxC unaccompanied by a fourth conserved cysteine. The charcteristic three-cysteine motif nucleates a [4Fe-4S] cluster, which binds SAM as a ligand to the unique Fe not ligated to a cysteine residue. The members participate in more than 40 distinct biochemical transformations, and most members have not been biochemically characterized. A handful of the members of this superfamily have been purified and at least partially characterized. Significant mechanistic and structural information is available for lysine 2,3-aminomutase, pyruvate formate-lyase, coproporphyrinogen III oxidase, and MoaA required for molybdopterin biosynthesis. Biochemical information is available for spore photoproduct lyase, anaerobic ribonucleotide reductase activation subunit, lipoyl synthase, and MiaB involved in methylthiolation of isopentenyladenine-37 in tRNA. The radical SAM enzymes biochemically characterized to date have in common the cleavage of the [4Fe-4S](1 +) -SAM complex to [4Fe-4S](2 +)-Met and the 5' -deoxyadenosyl radical, which abstracts a hydrogen atom from the substrate to initiate a radical mechanism.

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A Prevalent Peptide-Binding Domain Guides Ribosomal Natural Product Biosynthesis

Brandon J. Burkhart, Graham A Hudson, Kyle L Dunbar … (2015)

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a rapidly growing natural product class. RiPP precursor peptides can undergo extensive enzymatic tailoring, yielding structurally and functionally diverse products, and their biosynthetic logic makes them attractive bioengineering targets. Recent work suggests that unrelated RiPP modifying enzymes contain structurally similar precursor peptide-binding domains. Using profile hidden Markov model comparisons, we discovered related and previously unrecognized peptide-binding domains in proteins spanning the majority of known prokaryotic RiPP classes; thus, we named this conserved domain the RiPP precursor peptide recognition element (RRE). Through binding studies, we verify the role of the RRE for three distinct RiPP classes: linear azole-containing peptides, thiopeptides, and lasso peptides. Because numerous RiPP biosynthetic enzymes act on peptide substrates, our findings have powerful predictive value as to which protein(s) drive substrate binding, laying a foundation for further characterization of RiPP biosynthetic pathways and the rational engineering of new peptide-binding activities.