The metal delivery mechanism of transferrin and the role of bent metallocene metals towards anticancer activity – a theoretical exploration

Abstract

The metal delivery mechanism of the metalloenzyme transferrin and the antitumor active interaction of the metal ions, generated by the rapid hydrolysis of bent metallocene metals (Cp₂MCl₂; M = Ti, V, Nb, Mo), with the transferrin enzyme have been investigated. The initial and rate determining steps of the metal delivery mechanism have been identified. Comparisons are drawn between the antitumor action of various external metal ions and the role of the weak interactions that decide the site-specific decarboxylation reaction of transferrin have been investigated. Computational results reveal that the metal delivery mechanism starts by the site-specific concerted decarboxylation of transferrin leading to the thermodynamically unstable metal–oxo product and this unstable metal–oxo product delivers the metal ion to the nucleic acid via ATP. The computed reaction barriers for the decarboxylation step nicely correlate with the antitumor activity of the bent metallocenes.