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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 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 health sciences
UTAS Author:	Horne, J (Dr James Horne)
ID Code:	73987
Year Published:	2011
Web of Science® Times Cited:	16
Deposited By:	Central Science Laboratory
Deposited On:	2011-11-03
Last Modified:	2015-02-13
Downloads:	0