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1.D.33 The Channel-forming Polytheonamide B (Polytheonamide B) Family

Polytheonamide B, from the marine sponge, Theonella swinhoei, may form a β-helix that is stable in membranes (Oiki et al. 1997; Hamada et al. 2005). It forms channels with cation selectivity: H > Cs > Rb > K > Na (Oiki et al. 1997). Voltage-dependent transitions between brief openings and long closures were observed (Iwamoto et al. 2010; Matsuoka et al. 2011). It has been totally synthesized, and structural permutations have been designed (Ducho 2010; Inoue et al. 2010; Inoue 2011). Derivatives have been characterized with respect to their channel activities (Itoh et al. 2012; Shinohara et al. 2012).

Polytheonamide B (pTB), a highly cytotoxic polypeptide, is one of the most unusual nonribosomal peptides of sponge origin. pTB is a linear 48-residue peptide with alternating D- and L-amino acids and contains a total of eight types of nonproteinogenic amino acids. Hamada et al. (2010) determined the three-dimensional structure of pTB by NMR spectroscopy, structure calculation, and energy minimization. pTB adopts a single right-handed β(6.3)-helical structure in a 1:1 mixture of methanol/chloroform with a length of approximately 45 A and a hydrophilic pore of ca. 4 A inner diameter. These features indicate that pTB molecules form transmembrane channels that permeate monovalent cations as gramicidin A channels do. The strong cytotoxicity of pTB can be ascribed to its ability to form single molecule channels through biological membranes.

References associated with 1.D.33 family:

Ducho, C. (2010). Convergence leads to success: total synthesis of the complex nonribosomal peptide polytheonamide B. Angew Chem Int Ed Engl 49: 5034-5036. 20572229
Hamada, T., S. Matsunaga, G. Yano, and N. Fusetani. (2005). Polytheonamides A and B, highly cytotoxic, linear polypeptides with unprecedented structural features, from the marine sponge, Theonella swinhoei. J. Am. Chem. Soc. 127: 110-118. 15631460
Hamada, T., S. Matsunaga, M. Fujiwara, K. Fujita, H. Hirota, R. Schmucki, P. G√ľntert, and N. Fusetani. (2010). Solution structure of polytheonamide B, a highly cytotoxic nonribosomal polypeptide from marine sponge. J. Am. Chem. Soc. 132: 12941-12945. 20795624
Inoue, M. (2011). Total synthesis and functional analysis of non-ribosomal peptides. Chem Rec 11: 284-294. 21905205
Inoue, M., N. Shinohara, S. Tanabe, T. Takahashi, K. Okura, H. Itoh, Y. Mizoguchi, M. Iida, N. Lee, and S. Matsuoka. (2010). Total synthesis of the large non-ribosomal peptide polytheonamide B. Nat Chem 2: 280-285. 21124508
Itoh, H., S. Matsuoka, M. Kreir, and M. Inoue. (2012). Design, synthesis and functional analysis of dansylated polytheonamide mimic: an artificial peptide ion channel. J. Am. Chem. Soc. 134: 14011-14018. 22861006
Iwamoto, M., H. Shimizu, I. Muramatsu, and S. Oiki. (2010). A cytotoxic peptide from a marine sponge exhibits ion channel activity through vectorial-insertion into the membrane. FEBS Lett. 584: 3995-3999. 20699099
Matsuoka, S., N. Shinohara, T. Takahashi, M. Iida, and M. Inoue. (2011). Functional analysis of synthetic substructures of polytheonamide B: a transmembrane channel-forming peptide. Angew Chem Int Ed Engl 50: 4879-4883. 21520376
Oiki, S., I. Muramatsu, S. Matsunaga, and N. Fusetani. (1997). [A channel-forming peptide toxin: polytheonamide from marine sponge (Theonella swinhoei)]. Nihon Yakurigaku Zasshi 110Suppl1: 195P-198P. 9503431
Shinohara, N., H. Itoh, S. Matsuoka, and M. Inoue. (2012). Selective modification of the N-terminal structure of polytheonamide B significantly changes its cytotoxicity and activity as an ion channel. ChemMedChem 7: 1770-1773. 22489077