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


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.

참고문헌 (11)

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  8. 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 , J. Biol. Chem. / v.263,pp.19498-19504, 1988
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  10. Synthesis of 2,4,5-triphenyl-substituted oxazolidine and 2,5-diphenylsubstituted pyrrolidine derivatives. , Wittland, C., M. Arend, and N. Risch , Synthesis / v.3,pp.367-371, 1996
  11. Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. , Kivirikko, K. I., R. Myllyala, and T. Pihlajaniemi , FASEB J. / v.3,pp.1607-1617, 1989

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