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Degradation of Myoglobin by Polymeric Artificial Metalloproteases Containing Catalytic Modules with Various Catalytic Group Densities:  Site Selectivity in Peptide Bond Cleavage

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Contribution from the Department of Chemistry, Seoul National University, Seoul 151-747, Korea
Cite this: J. Am. Chem. Soc. 2003, 125, 47, 14580–14589
Publication Date (Web):November 1, 2003
https://doi.org/10.1021/ja034730t
Copyright © 2003 American Chemical Society
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    Abstract

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    Mononuclear, dinuclear, and tetranuclear artificial metalloproteases were prepared by attaching respective catalytic modules containing the Cu(II) complex of cyclen (Cu(II)Cyc) to a derivative of cross-linked polystyrene. The polymeric artificial metalloproteases effectively cleaved peptide bonds of myoglobin (Mb) by hydrolysis. The proteolytic activity increased considerably as the catalytic group density was raised:  the ratio of kcat/Km was 1:13:100 for the mono-, di-, and tetranuclear catalysts. In the degradation of Mb by the dinuclear catalyst, two pairs of intermediate proteins accumulated. One of the two initial cleavage sites leading to the formation of the protein fragments is identified as Gln(91)-Ser(92) and the other is suggested as Ala(94)-Thr(95). On the basis of a molecular modeling study by using the X-ray crystallographic structure of Mb, the site-selectivity is attributed to anchorage of one Cu(II)Cyc unit of the catalytic module to a heme carboxylate of Mb. The high site selectivity for the initial cleavage of a protein substrate and mechanistic analysis of the catalytic action are unprecedented for polymeric artificial enzymes.

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    Experimental procedures for synthesis of A(boc), B(boc), B, C(boc), C, and trans-cinnamoyl-l-Phe-Gly-Gly-l-Phe. This material is available free of charge via the Internet at http:/pubs.acs.org.

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