Regioselective protein oxidative cleavage enabled by enzyme-like recognition of an inorganic metal oxo cluster ligand

Shorok A. M. Abdelhameed, Francisco de Azambuja, Tamara Vasović, Nada D. Savić, Tanja Ćirković Veličković and Tatjana N. Parac-Vogt ()
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Shorok A. M. Abdelhameed: KU Leuven, Department of Chemistry, Celestijnenlaan 200F
Francisco de Azambuja: KU Leuven, Department of Chemistry, Celestijnenlaan 200F
Tamara Vasović: University of Belgrade - Faculty of Chemistry
Nada D. Savić: KU Leuven, Department of Chemistry, Celestijnenlaan 200F
Tanja Ćirković Veličković: University of Belgrade - Faculty of Chemistry
Tatjana N. Parac-Vogt: KU Leuven, Department of Chemistry, Celestijnenlaan 200F

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract Oxidative modifications of proteins are key to many applications in biotechnology. Metal-catalyzed oxidation reactions efficiently oxidize proteins but with low selectivity, and are highly dependent on the protein surface residues to direct the reaction. Herein, we demonstrate that discrete inorganic ligands such as polyoxometalates enable an efficient and selective protein oxidative cleavage. In the presence of ascorbate (1 mM), the Cu-substituted polyoxometalate K8[Cu2+(H2O)(α2-P2W17O61)], (CuIIWD, 0.05 mM) selectively cleave hen egg white lysozyme under physiological conditions (pH =7.5, 37 °C) producing only four bands in the gel electropherogram (12.7, 11, 10, and 5 kDa). Liquid chromatography/mass spectrometry analysis reveals a regioselective cleavage in the vicinity of crystallographic CuIIWD/lysozyme interaction sites. Mechanistically, polyoxometalate is critical to position the Cu at the protein surface and limit the generation of oxidative species to the proximity of binding sites. Ultimately, this study outlines the potential of discrete, designable metal oxo clusters as catalysts for the selective modification of proteins through radical mechanisms under non-denaturing conditions.

Date: 2023
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DOI: 10.1038/s41467-023-36085-z

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