Characterization of modification enzyme NukM and engineering of a novel thioether bridge in lantibiotic nukacin ISK-1
Division of Microbial Science and Technology, Department of Bioscience and Biotechnology, Faculty of Agriculture, Graduate School, Kyushu University, Higashi-ku, Fukuoka, Japan.Applied Microbiology and Biotechnology (Impact Factor: 3.34). 11/2009; 86(3):891-9. DOI: 10.1007/s00253-009-2334-8
The lantibiotic nukacin ISK-1 is an antimicrobial peptide containing unusual amino acids such as lanthionine and dehydrobutyrine. The nukacin ISK-1 prepeptide (NukA) undergoes posttranslational modifications, such as the dehydration and cyclization reactions required to form the unusual amino acids by the modification enzyme NukM. We have previously constructed a system for the introduction of unusual amino acids into NukA by coexpression of NukM in Escherichia coli. Using this system, we describe the substrate specificity of NukM by the coexpression of a series of NukA mutants. Our results revealed the following characteristics of NukM: (1) its dehydration activity is not coupled to its cyclization activity; (2) its dehydration activity is site-specific; (3) the length of the substrate is important for its dehydration activity. Furthermore, we succeeded in introducing a novel thioether bridge in NukA by replacing an unmodified Ser at position 27 with a Cys residue.
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ABSTRACT: Lantibiotics are ribosomally synthesized, post-translationally modified, peptide antibiotics containing unusual amino acids such as dehydrated amino acids and lanthionine. These unusual amino acids impose conformational constraints on the peptide and contribute to the biological activity and high physicochemical stability of lantibiotics. Recent researches on the modification enzymes responsible for dehydration and cyclization have considerably increased our understanding of their molecular characteristics and relaxed specificity. These insights enabled us to exploit these modification enzymes for developing new lantibiotic variants with improved therapeutic potential. Several methodologies have been explored to engineer novel lantibiotics. Here, we outline the current knowledge of modification enzymes. We also describe the methodologies and strategies used to engineer lantibiotics and provide some examples of successful generation of lantibiotics with enhanced activity.
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