Biotechnology and Bioprocess Engineering:BBE

  • 제5권1호
  • /
  • Pages.61-64
  • /
  • 2000
  • /
  • 1226-8372(pISSN)
  • /
  • 1976-3816(eISSN)
한국생물공학회 (The Korean Society for Biotechnology and Bioengineering)
권호 표지

Inhibition of Prolyl 4-Hydroxylase by Oxaproline Tetrapeptides In Vitro and Mass Analysis for the Enzymatic Reaction Products

  • Moon Hong-sik (Cheiljedang Institute of Technology) ;
  • Begley Tedhg P. (Department of Chemistry and Chemical Biology, Cornell University)
  • 발행 : 2000.01.01
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초록

A series of 5-oxaproline peptide derivatives was synthesized and evaluated for its ability to inhibit the prolyl 4-hydroxylase in vitro. Structure-activity studies show that the 5-oxaproline sequences, prepared by the 1,3-dipolar cycloaddition of the C-methoxycarbonyl-N-mannosyl nitrone in the presence of the ethylene, are more active than the corresponding proline derivatives. Prolyl 4-hydroxylase belongs to a family of $Fe^{2+}-dependent$ dioxygenase, which catalyzes the formation of 4-hydroxyproline in collagens by the hydroxylation of proline residues in -Gly-Xaa-Pro-Gly- of procollagen chains. In this paper we discover the more selective N-Cbz-Gly-Phe-Pro-Gly-OEt $(K_m\;=\;520\;{\mu}M)$ sequences which are showed stronger binding than others in vitro. Therefore, we set out to investigate constrained tetrapeptide that was designed to mimic the proline structure of pep tides for the development of prolyl 4-hydroxylase inhibitor. From this result, we found that the most potent inhibitor is N-Dansyl-Gly-Phe-5-oxaPro-Gly-OEt $(K_i\;=\;1.6\;{\mu}M)$. This has prompted attempts to develop drugs which inhibit collagen synthesis. Prolyl 4-hydroxylase would seem a particularly suitable target for antifibrotic therapy.

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참고문헌

  1. J. Med. Chem. v.35 Novel inhibitors of prolyl 4-hydroxylase. Cunliffe, C. J., T. J. Franklin, N. J. Hales, and G. B. Hill
  2. Annals Med. v.25 Collagens and their abnormalities in a wide spectrum of diseases. Kivirikko, K. I.
  3. J. Med. Chem. v.35 Eds. In collagen in health and disease; Churchill livingstone: Edinburgh 160-178; Dowell, R. I., and E. M. Hadley (1992) Novel inhibitors of prolyl 4-hydroxylase. Weiss, J. B. and M. I. V. Jayson
  4. FASEB J. v.3 Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. Kivirikko, K. I., R. Myllyala, and T. Pihlajaniemi
  5. Proc. Natl. Acad. Sci. U.S.A. v.89 Characterization of the human prolyl 4-hydroxylase tetramer and its multifunctional protein disulfide-isomerase subunit synthesized in a baculovirus expression system. Vuori, K., T. Pihlajaniemi, M. Marttila, and K. I. Kivirikko
  6. Biochem. J. v.251 Syncatalytic inactivation of prolyl 4-hydroxylase by anthracyclines. Gunzler, V., H. M. Hanauske-Abel, R. Myllyla, D. Kaska, A. Hanauske, and K. I. Kivirikko
  7. J. Biol. Chem. v.263 Syncatalytic inactivation of prolyl 4-hydroxylase by synthetic peptides containing the unphysiologic amino acid 5-oxaproline. Gunzler, V., D. Brocks, S. Henke, R. Myllyla, R. Geoiger, and K. I. Kivirikko
  8. J. Am. Chem. Soc. v.121 Mechanism-based inactivation of the human prolyl 4-hydroxylase by 5-oxaproline-containing peptides: Evidence for a prolyl radical intermediate. Wu, M., H. S. Moon, T. P. Begley, J. Myllyharju, and K. I. Kivirikko
  9. Synthesis v.3 Synthesis of 2,4,5-triphenyl-substituted oxazolidine and 2,5-diphenylsubstituted pyrrolidine derivatives. Wittland, C., M. Arend, and N. Risch
  10. Science v.266 Crystal and molecular structure of a collagen-like peptide at 1.9 Aresolution. Bella, J. M. Eaton, B. Brodsky, and H. M. Berman
  11. J. Theor. Biol. v.94 A stereochemical concept for the catalytic mechanism of prolyl hydroxylase. Applicability to classification and design of inhibitors. Hanauske-Abel, H. M. and V. A. Gunzler