Biomimetic synthesis of a peptide antibiotic, gratisin

Abstract

Recently, we reported the direct formation of a peptide antibiotic, gramicidin S (GS), cyclo(-D-Phe-Pro-Val-Orn-Leu-)₂, by the dimerization–cyclization of pentapeptide active esters, D-Phe-Pro-Val-Orn-Leu-ONSu (-ONSu: succinimide ester), having the sequence identical with that of the linear precursor pentapeptide in the biosynthesis of GS and no protecting group on the side-chain of the Orn residue. This biomimetic approach has been extended to the synthesis of a peptide antibiotic, gratisin (GR), cyclo(-D-Phe-Pro-D-Tyr-Val-Orn-Leu-)₂, isolated from Bacillus brevis Y-33. In the cyclization of six hexapeptide succinimide esters having a Val, Orn, Leu, D-Phe, Pro or D-Tyr residue at each C-terminus, only H-D-Phe-Pro-D-Tyr-Val-Orn-Leu-ONSu gave semi-GR and GR in yields of 31 and 8%, respectively. Other hexapeptide esters did not give semi-GR and GR. In both biomimetic syntheses of GS and GR, the amino acid sequences having a Leu residue at the C-terminus are essential. In addition, a change in the concentration of peptide and the polarity of reaction solvents influenced greatly the yields of cyclic monomer (semi-GR) and cyclic dimer (GR). However, the yield of GR by dimerization–cyclization of hexapeptide active ester was lower when compared with the direct formation of GS (38%). The difference may result from differences in the chain length and the configurations of amino acid residues around the Pro residue.

References

1. C. F. Gause and M. G. Brazhnikov, Am. Rev. Sov. Med., 1944, 2, 134; D. C. Hodgkin and B. M. Oughton, Biochem. J., 1957, 65, 752; S. Nozaki and I. Muramatsu, J. Antibiot., 1984, 37, 689; Bull. Chem. Soc. Jpn., 1985, 58, 331.
2. Amino acid residues with no prefix have the L-configuration. The abbreviations for amino acids and peptides are in accordance with the rules of the IUPAC-IUB Commission on Biological Nomenclature.
3. N. Izumiya, T. Kato, H. Aoyagi, M. Waki and M. Kondo, Synthetic Aspects of Biologically Active Cyclic Peptides-Gramicidin S and Tyrocidines, Kodansha, Tokyo and Halsted Press, New York, 1979, p. 49; M. Tamaki, M. Takimoto, M. Hayashi and I. Muramatsu, Bull. Chem. Soc. Jpn., 1989, 62, 594; M. Tamaki, S. Akabori and I. Muramatsu, Bull. Chem. Soc. Jpn., 1993, 66, 3113; Y. Minematsu, M. Waki, K. Suwa, T. Kato and N. Izumiya, Tetrahedron Lett., 1980, 21, 2179.
4. S. G. Laland, Ph. Frøyshov, C. Gilhuus-Moe and T. L. Zimmer, Nature (London) New Biol., 1972, 239, 43.
5. M. Tamaki, S. Akabori and I. Muramatsu, J. Am. Chem. Soc., 1993, 115, 10 492.
6. G. G. Zharikova, S. P. Myaskovskaya and A. B. Silaev, Vestn. Mosk. Univ. Ser. Biol. Pochvoved. Geol. Geogr., 1972, 27, 110(Chem. Abstr., 1972, 77, 162982p); S. P. Myaskovskaya, G. G. Zharikova and A. B. Silaev, Vestn. Mosk. Univ. Ser. Biol. Pochvoved. Geol. Geogr., 1973, 28, 123(Chem. Abstr., 1974, 80, 37446c); G. G. Zharikova, A. P. Zarubina, D. M. Kherat, S. P. Myaskovskaya and V. N. Maksimov, Antibiot. IKh Prod., 1975, 163(Chem. Abstr., 1976, 84, 119884r).
7. M. Tamaki, Bull. Chem. Soc. Jpn., 1984, 57, 3210; M. Tamaki, M. Takimoto and I. Muramatsu, Bull. Chem. Soc. Jpn., 1987, 60, 2101.
8. The cyclic monomers produced by the cyclization of the linear hexapeptide active esters 1 and 3–6 were found to have no antibiotic activity. On the other hand, H-Orn-Leu-D-Phe-Pro-D-Tyr-Val, isolated from a reaction mixture of peptide 2, showed the activities 1/4–1/8 of that of GR against Bacillus subtilis ATCC 6633, Streptomyces pyogenes N.Y.5, Staphylococcus aureus MS353 and Micrococcus luteus ATCC 9341.
9. M. Tamaki, S. Komiya, S. Akabori and I. Muramatsu, Bull. Chem. Soc. Jpn., 1997, 70, 899.
10. H. Kleinkauf and H. von Dohren, Eur. J. Biochem., 1990, 192, 1.
11. M. Tamaki, S. Akabori and I. Muramatsu, Bull. Chem. Soc. Jpn., 1991, 64, 583.