The reaction of the antimetastatic ruthenium(III) drug NAMI A with human H-chain ferritin (HuHf) was investigated through a variety of biophysical methods. We observed that the addition of HuHf to NAMI A solutions significantly increases the rate of spontaneous NAMI A hydrolysis suggesting the occurrence of a direct metallodrug–protein interaction. The resulting hydrolyzed Ru species binds the protein mostly forming a relatively tight 1 : 1 ruthenium/ferritin (subunit) adduct that was then separated and characterized. Notably, this adduct shows a characteristic CD spectrum in the visible region, which is diagnostic of the existence of at least one protein bound ruthenium center. The crystal structure of this NAMI A/HuHf adduct was subsequently solved at 1.58 Å resolution; clear evidence is given for the selective binding of a single Ru ion to His105 of each subunit with concomitant release of all other original Ru ligands in agreement with previous observations. We also noted that NAMI A produces a partial inhibition of HuHf ferroxidase activity. The implications of the above results are discussed.

The NAMI A-human ferritin system: A biophysical characterization / Ciambellotti, Silvia; Pratesi, Alessandro; Severi, Mirko; Ferraro, Giarita; Alessio, Enzo; Merlino, Antonello*; Messori, Luigi. - In: DALTON TRANSACTIONS. - ISSN 1477-9226. - ELETTRONICO. - 47:(2018), pp. 11429-11437. [10.1039/c8dt00860d]

The NAMI A-human ferritin system: A biophysical characterization

Ciambellotti, Silvia;Pratesi, Alessandro;Severi, Mirko;ALESSIO, ENZO;Merlino, Antonello
;
Messori, Luigi
2018

Abstract

The reaction of the antimetastatic ruthenium(III) drug NAMI A with human H-chain ferritin (HuHf) was investigated through a variety of biophysical methods. We observed that the addition of HuHf to NAMI A solutions significantly increases the rate of spontaneous NAMI A hydrolysis suggesting the occurrence of a direct metallodrug–protein interaction. The resulting hydrolyzed Ru species binds the protein mostly forming a relatively tight 1 : 1 ruthenium/ferritin (subunit) adduct that was then separated and characterized. Notably, this adduct shows a characteristic CD spectrum in the visible region, which is diagnostic of the existence of at least one protein bound ruthenium center. The crystal structure of this NAMI A/HuHf adduct was subsequently solved at 1.58 Å resolution; clear evidence is given for the selective binding of a single Ru ion to His105 of each subunit with concomitant release of all other original Ru ligands in agreement with previous observations. We also noted that NAMI A produces a partial inhibition of HuHf ferroxidase activity. The implications of the above results are discussed.
2018
47
11429
11437
Ciambellotti, Silvia; Pratesi, Alessandro; Severi, Mirko; Ferraro, Giarita; Alessio, Enzo; Merlino, Antonello*; Messori, Luigi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1134283
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