ORGN 534 |
| Claire E. Milne1, Zohreh Hojati2, Lyndsey Gordon2, John Jim2, Gabriel Uguru1, Colin P. Smith2, and Jason Micklefield1. (1) Department of Chemistry, University of Manchester Institute of Science and Technology (UMIST), PO Box 88, Manchester, M60 1QD, United Kingdom, (2) Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology (UMIST), PO Box 88, Manchester, M60 1QD, United Kingdom |
| 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 clinical trials. By disrupting the biosynthetic pathway for HPG biosynthesis it was possible to generate novel CDA variants by a mutasynthesis approach. In addition 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 respectively, which provide the first clear experimental evidence of how nature evolves new nonribosomal peptides by recombination of homologous NRPS genes. |
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Bioorganic, Molecular Recognition, Asymmetric Reactions and Syntheses
11:00 AM-1:00 PM, Wednesday, September 10, 2003 Javits Convention Center -- Hall 1B/1C, Poster
Division of Organic Chemistry |