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

Moon Hong-sik; Begley Tedhg P.

doi:10.1007/bf02932356

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

Biotechnology and bioprocess engineering : Bbe, v.5 no.1, 2000년, pp.61 - 64

Moon Hong-sik (Cheiljedang Institute of Technology) , Begley Tedhg P. (Department of Chemistry and Chemical Biology, Cornell University)

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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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After 30 min incubation, 250 μL of the reaction mixture was removed from 500 μL of the incubation solution and it was mixed with 250 μL methylene chloride in order to separate the organic phase. The enzymatic reaction was confirmed by TLC (7% methanol in methylene chloride) and FAB mass spectroscopy [N-Cbz-Gly-Phe-Pro-Gly-OEt : HRMS (M+l) = 539.2509 to N-Cbz-Gly-Phe-4-hydroxyPro-Gly-OEt: HRMS(M+1) = 555.2456, Fig. 1].

참고문헌 (11)

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DOI : 10.1007/BF02932356 [무료]
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