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

• 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
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja026249t

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.