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Characterization of the N-Methyltransferase Activities of the Multifunctional Polypeptide Cyclosporin Synthetase

Citation

Velkov, T and Horne, J and Scanlon, MJ and Capuano, B and Yuriev, E and Lawen, A, Characterization of the N-Methyltransferase Activities of the Multifunctional Polypeptide Cyclosporin Synthetase , Chemistry and Biology, 18, (4) pp. 464-475. ISSN 1074-5521 (2011) [Refereed Article]


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Copyright Statement

Copyright 2011 Elsevier Ltd

DOI: doi:10.1016/j.chembiol.2011.01.017

Abstract

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.

Item Details

Item Type:Refereed Article
Research Division:Chemical Sciences
Research Group:Medicinal and Biomolecular Chemistry
Research Field:Biologically Active Molecules
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Horne, J (Dr James Horne)
ID Code:73987
Year Published:2011
Web of Science® Times Cited:6
Deposited By:Central Science Laboratory
Deposited On:2011-11-03
Last Modified:2015-02-13
Downloads:0

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