1. Characterization of the N-Methyltransferase Activities of the Multifunctional Polypeptide Cyclosporin Synthetase
- Author
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Velkov, Tony, Horne, James, Scanlon, Martin J., Capuano, Ben, Yuriev, Elizabeth, and Lawen, Alfons
- Subjects
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METHYLTRANSFERASES , *LIGASES , *METHYLATION , *BIOSYNTHESIS , *CYCLOSPORINE , *CHEMICAL bonds , *MOLECULAR models - Abstract
Summary: This study demonstrates a critical role for N-methylation in cyclosporin biosynthesis and maintenance of the biologically active cyclosporin conformation. The structural requirements for the AdoMet binding to CySyn were defined. N-methylation of specific amide positions in the cyclosporin backbone is critical for the complete assembly and cyclization of the cyclosporin peptide. A maximum of two desmethyl positions is tolerated before peptide assembly stalls. Subinhibitory concentrations of AdoMet analogs directed peptide assembly towards cyclosporins with less than seven N-methylated amide bonds. Molecular modeling and nuclear magnetic resonance analyses indicate that N-methylation of specific amide bond positions in the cyclosporin backbone is mandatory for the formation of a product-like conformation and recognition by the acceptor site of the downstream peptide bond forming C-domain. [Copyright &y& Elsevier]
- Published
- 2011
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