A peptide ligase and the ribosome cooperate to synthesize the peptide pheganomycin

Motoyoshi Noike, Takashi Matsui, Koichi Ooya, Ikuo Sasaki, Shouta Ohtaki, Yoshimitsu Hamano, Chitose Maruyama, Jun Ishikawa, Yasuharu Satoh, Hajime Ito, Hiroyuki Morita, Tohru Dairi

    Research output: Contribution to journalArticlepeer-review

    21 Citations (Scopus)

    Abstract

    Peptide antibiotics are typically biosynthesized by one of two distinct machineries in a ribosome-dependent or ribosome-independent manner. Pheganomycin (PGM (1)) and related analogs consist of the nonproteinogenic amino acid (S)-2-(3,5-dihydroxy-4-hydroxymethyl)phenyl-2-guanidinoacetic acid (2) and a proteinogenic core peptide, making their origin uncertain. We report the identification of the biosynthetic gene cluster from Streptomyces cirratus responsible for PGM production. Unexpectedly, the cluster contains a gene encoding multiple precursor peptides along with several genes plausibly encoding enzymes for the synthesis of amino acid 2. We identified PGM1, which has an ATP-grasp domain, as potentially capable of linking the precursor peptides with 2, and validate this hypothesis using deletion mutants and in vitro reconstitution. We document PGM1's substrate permissivity, which could be rationalized by a large binding pocket as confirmed via structural and mutagenesis experiments. This is to our knowledge the first example of cooperative peptide synthesis achieved by ribosomes and peptide ligases using a peptide nucleophile.

    Original languageEnglish
    Pages (from-to)71-76
    Number of pages6
    JournalNature Chemical Biology
    Volume11
    Issue number1
    DOIs
    Publication statusPublished - 2015 Jan 1

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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