Metabolism and Mechanism of Action of Neplanocin A — A Potent Inhibitor of S-Adenosylhomocysteine Hydrolase

  • Bradley T. Keller
  • Ronald T. Borchardt
Chapter
Part of the Experimental Biology and Medicine book series (EBAM, volume 12)

Abstract

Neplanocin A [(-)-9-[trans-2, trans-3-dihydroxy-4-(hydroxymethyl) cyclopent-4-enyl] adenine] (Figure 1) is a cyclopentenyl analog of adenosine which has been isolated from the culture filtrate of the microorganism Ampullariella regularis (Yaginuma et al., 1980, 1981; Hayashi et al., 1981). Despite having minimal antibacterial and antifungal activity, this novel antibiotic was initially observed to be cytotoxic at 0.2 µg/ml against cultured L5178Y lymphoma cells (Yaginuma et al., 1981). It also exhibited significant antitumor activity in mice bearing L1210 leukemia, increasing the life span by 120% at 5 mg/kg/day (Tsujino et al., 1980; Yaginuma et al., 1981).

Keywords

Adenosine Methionine NADH Adenine Homocysteine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aarbakke, J., Gordon, R.K., Cross, A.S., Miura, G.A. and Chiang, P.K. (1985) Fed. Proc. 44. 464, abst.#313.Google Scholar
  2. Bartel, R.L. and Borchardt, R.T. (1985) Anal. Biochem. 149.191–196.PubMedCrossRefGoogle Scholar
  3. Borchardt, R.T. (1979) J. Amer. Chem. Soc. 101.458–463.CrossRefGoogle Scholar
  4. Borchardt, R.T. and Pugh, C.S.G. (1979) in Transmethylation (Usdin, E., Borchardt, R.T. and Creveling, C.R., eds.) pp. 197–206, Elsevier/North-Holland, New York.Google Scholar
  5. Borchardt, R.T., Keller, B.T. and Patel-Thombre, U. (1984) J. Biol. Chem. 259, 4353–4358.PubMedGoogle Scholar
  6. De Clercq, E. (1985) Antimicrob. Agents Chemother. 28. 84–89.PubMedGoogle Scholar
  7. De Clercq, E. and Cools, M. (1985) Biochem. Biophys. Res. Commun. 129. 306–311.PubMedCrossRefGoogle Scholar
  8. De Clercq, E. and Montgomery, J.A. (1983) Antiviral Res. 3,17–24.PubMedCrossRefGoogle Scholar
  9. De Clercq, E., Descamps, J., De Somer, P. and Holy, A. (1978) Science 200. 563–565.CrossRefGoogle Scholar
  10. Glazer, R.I. and Knode, M.C. (1984) J. Biol. Chem. 259.12964–12969.PubMedGoogle Scholar
  11. Hayashi, M., Yaginuma, S., Yishioka, H. and Nakatsu, K. (1981) J. Antibiot. (Tokvo) 34, 675–680.Google Scholar
  12. Hohman, R.J., Guitton, M.C. and Vernon, M. (1985) Proc. Natl. Acad. Sei. USA. 82, 4578–4581.CrossRefGoogle Scholar
  13. Keller, B.T. and Borchardt, R.T. (1983) Fed. Proc. 42. 2139, abst.#2230.Google Scholar
  14. Keller, B.T. and Borchardt, R.T. (1984) Biochem. Biophys. Res. Commun. 120. 131–137.PubMedCrossRefGoogle Scholar
  15. Keller, B.T., Clark, R.S., Pegg, A.E. and Borchardt, R.T. (1985) Mol. Pharmacol, 28, 364–370.PubMedGoogle Scholar
  16. Ramakrishnan, V. and Borchardt, R.T. (1984) Fed. Proc. 43. 1556, abst. #814.Google Scholar
  17. Rice, A.P. and Roberts, B.E. (1983) J. Virology 47. 529–539.PubMedGoogle Scholar
  18. Saunders, P.P., Tan, M.T. and Robins, R.K. (1985) Biochem. Pharmacol. 34, 2749–2754.PubMedCrossRefGoogle Scholar
  19. Tsujino, M., Yaginuma, S., Fujii, T., Hayano, K., Matsudo, T., Watanabe, T. and Abe, J. (1980) in Current Chemotherapy and Infectious Disease. Proceedings of the 11 th International Congress of Chemotherapy (Nelson, J.D. and Grassi, C., eds.) Vol. 2, pp. 1559–1561, The American Society for Microbiology, Washington, DC.Google Scholar
  20. Whaun, J.M., Miura, G.A., Brown, N.D., Gordon, R.K. and Chiang, P.K.. (1985) Fed. Proc. 44. 499, abst.#516.Google Scholar
  21. Yaginuma, S., Tsujino, M., Muto, N., Otani, M., Hayashi, M., Ishimura, F., Fujii, T., Watanabe, S., Matsuda, T., Watanabe, T. and Abe, J. (1980) in Current Chemotherapy and Infectious Disease. Proceedings of the 11 th International Congress of Chemotherapy (Nelson, J.D. and Grassi, C., eds.) Vol. 2, pp. 1558–1559, The American Society for Microbiology, Washington, DC.Google Scholar
  22. Yaginuma, S., Muto, N., Tsujino, M., Sudate, Y., Hayashi, M. and Otani, M. (1981) J. Antibiot. (Tokyo) 34, 359–366.Google Scholar

Copyright information

© The Humana Press Inc. 1986

Authors and Affiliations

  • Bradley T. Keller
    • 1
  • Ronald T. Borchardt
    • 1
  1. 1.Departments of Biochemistry and Pharmaceutical ChemistryUniversity of KansasLawrenceUSA

Personalised recommendations