Isovaline in naturally occurring peptides: A nondestructive methodology for configurational assignment

Abstract

The nonproteinogenic, C(α)-tetrasubstituted, helicogenic, chiral α-amino acid isovaline (Iva) is remarkably spread in the biosphere. Together with its achiral, lower homolog α-aminoisobutyric acid (Aib), it represents a characteristic marker of a class of naturally occurring peptide antibiotics, for which the acronym "peptaibiotics" became established. In these peptides, Iva occurs as the (S)-(= L) or the (R)-(= D) enantiomer, but peptide sequences containing both Iva enantiomers are also common. Here, we applied our recently developed (1)H-NMR method, which enables the nondestructive assignment of the configuration of each Iva residue in a peptide of known helical screw sense, to natural and synthetic peptaibiotics. Our method proved to be generally applicable and provided evidence that, in the peptaibiotic bergofungin A, the Iva(12) configuration is (R) and not (S) as reported previously. Moreover, we extended our NMR method by including a (13)C-NMR parameter. A statistical analysis of the preferred main- and side-chain conformations of the Iva residues in peptides, performed based on their published X-ray diffraction structures, allowed us to provide a sound rationale to the NMR criteria exploited to establish the configuration of this amino acid.