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Chem Biol. 2011 Apr 22;18(4):464-75. doi: 10.1016/j.chembiol.2011.01.017.

Characterization of the N-methyltransferase activities of the multifunctional polypeptide cyclosporin synthetase.

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  • 1Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia. Tony.Velkov@monash.edu.au

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.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
21513883
[PubMed - indexed for MEDLINE]
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