Conformation and Absolute Configuration of Nocathiacin I Determined by NMR Spectroscopy and Chiral Capillary Electrophoresis

Nocathiacin I (BMS-249524) is a highly cross-linked thiazolyl peptide that displays potent activity against Gram-positive bacteria, including a number of antibiotic-resistant strains. This natural product contains 10 chiral centers. NMR studies have been performed to characterize the solution struct...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2002-06, Vol.124 (25), p.7284-7285
Main Authors: Constantine, Keith L, Mueller, Luciano, Huang, Stella, Abid, Sadia, Lam, Kin S, Li, Wenying, Leet, John E
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Chemistry
Electrophoresis, Capillary
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Medical sciences
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular - methods
Organic chemistry
Peptides
Peptides, Cyclic - chemistry
Pharmacology. Drug treatments
Preparations and properties
Protein Conformation
Stereoisomerism
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Summary:Nocathiacin I (BMS-249524) is a highly cross-linked thiazolyl peptide that displays potent activity against Gram-positive bacteria, including a number of antibiotic-resistant strains. This natural product contains 10 chiral centers. NMR studies have been performed to characterize the solution structure of nocathiacin I. A uniformly 13C,15N-labeled sample was used to obtain NMR assignments. Restrained simulated annealing calculations were performed by using accurately determined NOE distance restraints. All of the chiral centers were allowed to float during the simulated annealing protocol. Two clusters of structures were obtained that satisfy the NOE restraints very well and that are reasonably consistent with vicinal J-coupling constants. Within each cluster, all 10 chiral centers are uniquely defined. The two clusters are effectively mirror images of each other:  all chiral centers that have the R(S) configuration in one cluster have the S(R) configuration in the other. The single threonine residue in nocathiacin I was subsequently determined to be l-threonine by chiral capillary electrophoresis, allowing the absolute configurations of all 10 chiral centers to be defined.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja026249t