Structure, biosynthetic origin and engineered biosynthesis of Calcium Dependent Antibiotic from Streptomyces coelicolor.

Claire E. Milne, Zohreh Hojati, Lyndsey Gordon, John Jim, Gabriel Uguru, Colin P. Smith, Jason Micklefield

    Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

    Abstract

    The calcium dependent antibiotic (CDA) is a cyclic undecapeptide comprising of an unusual 2,3 epoxyhexanoyl fatty acid side chain and several non-proteinogenic amino acid residues including D-4-hydroxyphenylglycine, D-3-phosphohydroxyasparagine and L-3-methylglutamic acid. CDA is structurally similar to daptomycin, another lipopeptide antibiotic in phase III clin. trials. By disrupting the biosynthetic pathway for HPG biosynthesis it was possible to generate novel CDA variants by a mutasynthesis approach. In addn. the engineered biosynthesis of new CDAs has been achieved by active site modification of the key nonribosomal peptide synthetase (NRPS) adenylation (Ad) domains. During this work evidence of a hitherto illusive NRPS proof reading mechanism was also discovered. Finally ring expanded and contracted CDAs (10mer and 12mer) where generated by mutants which had undergone rare module amplification and deletion events resp., which provide the first clear exptl. evidence of how nature evolves new nonribosomal peptides by recombination of homologous NRPS genes. [on SciFinder (R)]
    Original languageEnglish
    Title of host publicationAbstracts of Papers, 226th ACS National Meeting, New York, NY, United States, September 7-11, 2003
    Publication statusPublished - 2003

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