The NAMI A - human ferritin system: a biophysical characterization

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 occ...

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Published in:Dalton transactions : an international journal of inorganic chemistry 2018, Vol.47 (33), p.11429-11437
Main Authors: Ciambellotti, Silvia, Pratesi, Alessandro, Severi, Mirko, Ferraro, Giarita, Alessio, Enzo, Merlino, Antonello, Messori, Luigi
Format: Article
Language:English
Subjects:
Crystal structure
Diagnostic systems
Ferritin
Proteins
Ruthenium
Selective binding
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Summary: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/HuHf adduct with selective binding of a Ru ion to His105 is described. This adduct is of potential pharmaceutical interest as a carrier of ruthenium ions.
ISSN:1477-9226
1477-9234
DOI:10.1039/c8dt00860d