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Bioinformatic Atlas of Radical SAM Enzyme-Modified RiPP Natural Products Reveals an Isoleucine–Tryptophan Crosslink

Clark, Kenzie A. ; Seyedsayamdost, Mohammad R.

Journal of the American Chemical Society, 2022-10, Vol.144 (39), p.17876-17888 [Periódico revisado por pares]

American Chemical Society

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  • Título:
    Bioinformatic Atlas of Radical SAM Enzyme-Modified RiPP Natural Products Reveals an Isoleucine–Tryptophan Crosslink
  • Autor: Clark, Kenzie A. ; Seyedsayamdost, Mohammad R.
  • É parte de: Journal of the American Chemical Society, 2022-10, Vol.144 (39), p.17876-17888
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing family of natural products with diverse activities and structures. RiPP classes are defined by the tailoring enzyme, which can introduce a narrow range of modifications or a diverse set of alterations. In the latter category, RiPPs synthesized by radical S-adenosylmethionine (SAM) enzymes, known as RaS-RiPPs, have emerged as especially divergent. A map of all RaS-RiPP gene clusters does not yet exist. Moreover, precursor peptides remain difficult to predict using computational methods. Herein, we have addressed these challenges and report a bioinformatic atlas of RaS-RiPP gene clusters in available microbial genome sequences. Using co-occurrence of RaS enzymes and transporters from varied families as a bioinformatic hook in conjunction with an in-house code to identify precursor peptides, we generated a map of ∼15,500 RaS-RiPP gene clusters, which reveal a remarkable diversity of syntenies pointing to a tremendous range of enzymatic and natural product chemistries that remain to be explored. To assess its utility, we examined one family of gene clusters encoding a YcaO enzyme and a RaS enzyme. We find the former is noncanonical, contains an iron–sulfur cluster, and installs a novel modification, a backbone amidine into the precursor peptide. The RaS enzyme was also found to install a new modification, a C–C crosslink between the unactivated terminal δ-methyl group of Ile and a Trp side chain. The co-occurrence search can be applied to other families of RiPPs, as we demonstrate with the emerging DUF692 di-iron enzyme superfamily.
  • Editor: American Chemical Society
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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