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Characterization of the N-Methyltransferase Activities of the Multifunctional Polypeptide Cyclosporin Synthetase
journal contribution
posted on 2023-05-17, 08:53 authored by Velkov, T, Henry HorneHenry Horne, Scanlon, MJ, Capuano, B, Yuriev, E, Lawen, AThis 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.
History
Publication title
Chemistry and BiologyVolume
18Issue
4Pagination
464-475ISSN
1074-5521Publisher
Cell PressPlace of publication
1100 Massachusetts Ave, Cambridge, USA, Ma, 02138Rights statement
Copyright 2011 Elsevier LtdRepository Status
- Restricted