Polytheonamides A and B, Highly Cytotoxic, Linear Polypeptides with Unprecedented Structural Features, from the Marine Sponge,Theonellaswinhoei

Abstract

Polytheonamides A and B are highly cytotoxic polypeptides with 48 amino acid residues isolated from the marine sponge, Theonella swinhoei. The structure of polytheonamide B was determined by spectral and chemical methods, especially extensive 2D NMR experiments, which resulted in the unprecedented polypeptide structure; the N-terminal glycine blocked with a 5,5-dimethyl-2-oxo-hexanoyl group, the presence of eight tert-leucine, three beta-hydroxyvaline, six gamma-N-methylasparagine, two gamma-N-methyl-beta-hydroxyasparagine, and beta,beta-dimethymethionine sulfoxide residues. More significantly, it has the sequence of alternating D- and L-amino acids. Polytheonamide A is an epimer of polytheonamide B differing only in the stereochemistry of the sulfoxide of the 44(th) residue.

Nichtproteinogene Aminosäurebausteine für Peptidgerüste aus nichtribosomalen Peptiden und hybriden Polyketiden

“…[117] . [120,121] wahrscheinlich durch posttranslationale C-Methylierung von Valinseitenketten am b-Kohlenstoff über einen radikalischen, SAMvermittelten Transfer von CH 3 C-Gruppen gebildet (Schema 8 B). Eine analoge C-Methylierung einer Ile-Seitenkette zur entsprechend verzweigten Seitenkette kommt ebenfalls vor.…”

Functional Analysis of Synthetic Substructures of Polytheonamide B: A Transmembrane Channel‐Forming Peptide

“…Intriguingly, the sequence has alternating d-and l-amino acid residues, except for the eight glycine units. [2] These unique structural features enable 1 to fold into a distinctive three-dimensional structure not found in ribosomal proteins. Extensive NMR and modeling experiments by Hamada …”

“…Overall, compound 10 exhibited H + -channel activity analogous to that of 1 except for its weak voltage dependency. Most importantly, it was found that the hydrophobic N-terminal region Ncap- [1][2][3][4][5][6][7][8][9][10][11], which is responsible for the significant difference in the cytotoxicity of 1 and 10, is not an essential component for channel formation.…”

“…While the C-terminus substructures are characterized by membrane-disrupting activity up to the length of 8, the Nterminally elongated peptides as in 10 and 1 are conferred with ion-channel activity and devoid of membrane-disrupting activity. Furthermore, the hydrophobic Ncap- [1][2][3][4][5][6][7][8][9][10][11] region of 1 was found responsible for rendering 1 11 000 times more cytotoxic than 10, presumably by aiding the peptide to partition into the hydrophobic membrane environment. Therefore, the channel-forming property of 10 and the role of the N-terminus region of 1 in membrane partitioning represent the two most important findings, which provide new design principles for the synthesis of artificial ion-channelforming molecules.…”

Konvergenz führt zum Erfolg: Totalsynthese des komplexen nicht‐ribosomalen Peptids Polytheonamid B

“…[1] Die Polytheonamide A und B sind die wahrscheinlich größten und strukturell komplexesten bekannten nicht-ribosomalen Peptide. [2] Sie wurden aus dem marinen Schwamm Theonella swinhoei isoliert, in dem sie möglicherweise von einem noch unbekannten symbiotischen Mikroorganismus produziert werden. Sie bestehen aus 48 Aminosäuren und einer N-terminalen 5,5-Dimethyl-2-oxohexanoyl-Einheit (Abbildung 1).…”